1. Field of the Invention
This invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4.
2. References
The following publications, patents and patent applications are cited in this application as superscript numbers:
1 Hemler and Takada, European Patent Application Publication No. 330,506, published Aug. 30, 1989
2 Elices, et al., Cell, 60:577-584 (1990)
3 Springer, Nature, 346:425-434 (1990)
4 Osborn, Cell, 62:3-6 (1990)
5 Vedder, et al., Surgery, 106:509 (1989)
6 Pretolani, et al., J. Exp. Med., 180:795 (1994)
7 Abraham, et al., J. Clin. Invest., 93:776 (1994)
8 Mulligan, et al., J. Immunology, 150:2407 (1993)
9 Cybulsky, et al., Science, 251:788 (1991)
10 Li, et al., Arterioscier. Thromb., 13:197 (1993)
11 Sasseville, et al., Am. J. Path., 144:27 (1994)
12 Yang, et al., Proc. Nat. Acad. Science (USA), 90:10494 (1993)
13 Burkly, et al., Diabetes, 43:529 (1994)
14 Baron, et al., J. Clin. Invest., 93:1700 (1994) 15 Hamann, et al., J. Immunology, 152:3283 (1994)
16 Yednock, et al., Nature, 356:63 (1992)
17 Baron, et al., J. Exp. Med., 177:57 (1993)
18 van Dinther-Janssen, et al., J. Immunology. 147:4207 (1991)
19 van Dinther-Janssen, et al., Annals. Rheumatic Dis., 52:672 (1993)
20 Elices, et al., J. Clin. Invest., 93:405 (1994)
21 Postigo, et al., J. Clin. Invest., 89:1445 (1991)
22 Paul, et al., Transpl. Proceed., 25:813 (1993)
23 Okarhara, et al., Can. Res., 54:3233 (1994)
24 Paavonen, et al., Int. J. Can., 58:298 (1994)
25 Schadendorf, et al., J. Path., 170:429 (1993)
26 Bao, et al., Diff., 52:239 (1993)
27 Lauri, et al., British J. Cancer, 68:862 (1993)
28 Kawaguchi, et al., Japanese J. Cancer Res., 83:1304 (1992)
29 Kogan, et al., U.S. Pat. No. 5,510,332, issued Apr. 23, 1996
30 International Patent Appl. Publication No. WO 96/01644
All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
3. State of the Art
VLA-4 (also referred to as xcex14xcex21 integrin and CD49d/CD29), first identified by Hemler and Takada1 is a member of the xcex21 integrin family of cell surface receptors, each of which comprises two subunits, an xcex1 chain and a xcex2 chain. VLA4 contains an xcex14 chain and a xcex21 chain. There are at least nine xcex21 integrins, all sharing the same xcex21 chain and each having a distinct xcex1 chain. These nine receptors all bind a different complement of the various cell matrix molecules, such as fibronectin, laminin, and collagen. VLA-4, for example, binds to fibronectin. VLA-4 also binds non-matrix molecules that are expressed by endothelial and other cells. These non-matrix molecules include VCAM-1, which is expressed on cytokine-activated human umbilical vein endothelial cells in culture. Distinct epitopes of VLA-4 are responsible for the fibronectin and VCAM-1 binding activities and each activity has been shown to be inhibited independently.2 
Intercellular adhesion mediated by VLA-4 and other cell surface receptors is associated with a number of inflammatory responses. At the site of an injury or other inflammatory stimulus, activated vascular endothelial cells express molecules that are adhesive for leukocytes. The mechanics of leukocyte adhesion to endothelial cells involves, in part, the recognition and binding of cell surface receptors on leukocytes to the corresponding cell surface molecules on endothelial cells. Once bound, the leukocytes migrate across the blood vessel wall to enter the injured site and release chemical mediators to combat infection. For reviews of adhesion receptors of the immune system, see, for example, Springer3 and Osborn4.
Inflammatory brain disorders, such as experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS) and meningitis, are examples of central nervous system disorders in which the endothelium/leukocyte adhesion mechanism results in destruction to otherwise healthy brain tissue. Large numbers of leukocytes migrate across the blood brain barrier (BBB) in subjects with these inflammatory diseases. The leukocytes release toxic mediators that cause extensive tissue damage resulting in impaired nerve conduction and paralysis.
In other organ systems, tissue damage also occurs via an adhesion mechanism resulting in migration or activation of leukocytes. For example, it has been shown that the initial insult following myocardial ischemia to heart tissue can be further complicated by leukocyte entry to the injured tissue causing still further insult (Vedder et al.5). Other inflammatory or medical conditions mediated by an adhesion mechanism include, by way of example, asthma6-1, Alzheimer""s disease, atherosclerosis9-10, AIDS dementia11, diabetes12-4 (including acute juvenile onset diabetes), inflammatory bowel disease15 (including ulcerative colitis and Crohn""s disease), multiple sclerosis16-17, rheumatoid arthritis18-21, tissue transplantation22, tumor metastasis23-28, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
In view of the above, assays for determining the VLA-4 level in a biological sample containing VLA-4 would be useful, for example, to diagnosis VLA-4 mediated conditions. Additionally, despite these advances in the understanding of leukocyte adhesion, the art has only recently addressed the use of inhibitors of adhesion in the treatment of inflammatory brain diseases and other inflammatory conditions29-30. The present invention addresses these and other needs.
This invention provides compounds which bind to VLA-4. Such compounds can be used, for example, to assay for the presence of VLA-4 in a sample and in pharmaceutical compositions to inhibit cellular adhesion mediated by VLA-4, for example, binding of VCAM-1 to VLA-4. The compounds of this invention have a binding affinity to VLA-4 as expressed by an IC50 of about 15 xcexcM or less (as measured using the procedures described in Example A below).
Accordingly, in one of its method aspects, this invention is directed to a method for treating a disease mediated by VLA-4 in a patient, which method comprises administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula Ia and/or Ib: 
wherein, in formula Ia, R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic;
in formula Ib, R1 and R2, together with the carbon atom and Wxe2x80x2 to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic;
and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula Ia or Ib is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(G)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where each R is independently hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, xe2x80x94N[S(O)2xe2x80x94Rxe2x80x2]2 and xe2x80x94N[S(O)2xe2x80x94NRxe2x80x2]2 where each Rxe2x80x2 is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
R3 and R3xe2x80x2 are independently selected from the group consisting of hydrogen, isopropyl, xe2x80x94CH2Z where Z is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and
where R3 and R3 are joined to form a substituent selected from the group consisting of xe2x95x90CHZ where Z is defined above provided that Z is not hydroxyl or thiol, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic and substituted heterocyclic;
Q is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2, and xe2x80x94NR4xe2x80x94;
R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic or, optionally, R4 and R1 or R4 and R2, together with the atoms to which they are bound, are joined to form a heteroaryl, a substituted heteroaryl, a heterocyclic or a substituted heterocyclic group;
W is selected from the group consisting of nitrogen and carbon; and
Wxe2x80x2 is selected from the group consisting of nitrogen, carbon, oxygen, sulfur, S(O), and S(O)2;
X is selected from the group consisting of hydroxyl, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy and xe2x80x94NRxe2x80x3Rxe2x80x3 where each Rxe2x80x3 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
and enantiomers, diastereomers and pharmaceutically acceptable salts thereof;
and further wherein the compound of formula Ia and/or Ib has a binding affinity to VLA-4 as expressed by an IC50 of about 15 xcexcM or less.
Preferably, in the above method, R3 is xe2x80x94(CH2)xxe2x80x94Arxe2x80x94R9, where Ar is aryl, substituted aryl, heteroaryl and substituted heteroaryl; R9 is selected from the group consisting of acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxythiocarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl; and x is an integer from 0 to 4. R3xe2x80x2 is preferably alkyl or hydrogen; more preferably, R3xe2x80x2 is hydrogen.
More preferably, R3 is a group of the formula: 
wherein R9 and x are as defined herein. Preferably, R9 is in the para position of the phenyl ring; and x is an integer of from 1 to 4, more preferably, x is 1.
In a preferred embodiment, R9 is selected from xe2x80x94Oxe2x80x94Zxe2x80x94NR11R11xe2x80x2 and xe2x80x94Oxe2x80x94Zxe2x80x94R12 wherein R11 and R11xe2x80x2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, and where R11 and R11xe2x80x2 are joined to form a heterocycle or a substituted heterocycle, R12 is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of xe2x80x94C(O)xe2x80x94 and xe2x80x94SO2xe2x80x94. More preferably, R9 is xe2x80x94OC(O)NR11R11xe2x80x2, wherein R11 and R11xe2x80x2 are as defined herein.
In the above method, Z is preferably xe2x80x94C(O)xe2x80x94. Preferably, Q is xe2x80x94NR4xe2x80x94.
In a preferred embodiment, the above method employs a compound of formula IIa or IIb: 
wherein R3, R3xe2x80x2 and X are as defined herein;
ring A and ring B independently form a heteroaryl or substituted heteroaryl group having two nitrogen atoms in the heteroaryl ring;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and xe2x80x94SO2R10 where R10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
or optionally, one of, R4 and ring A, R4 and R5, R4 and R6, or R1 and R6, together with the atoms to which they are bound, can be joined to form a heterocyclic or substituted heterocyclic ring;
and enantiomers, diastereomers and pharmaceutically acceptable salts thereof; and provided that ring B does not form a 6-amino or substituted amino pyrimidin-4-yl group.
Preferably, ring A forms a pyridazine, pyrimidine or pyrazine ring; more preferably, a pyrimidine or pyrazine ring; wherein the pyridazine, pyrimidine or pyrazine ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen.
Preferably, ring B forms a pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or a 1,1-dioxo-1,2,5-thiadiazole ring; more preferably, a pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or a 1,1-dioxo-1,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine or pyrazine ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen.
In another preferred embodiment, the method employs a compound of formula IIIa, IIIc, IIId, IIIe or IIIf: 
wherein R3, R3xe2x80x2 and X are as defined herein;
R4xe2x80x2 is selected from the group consisting of hydrogen and alkyl or, optionally, one of, R4xe2x80x2 and R5, R4xe2x80x2 and R6, R5 and R6, R5 and R8, or R6 and R8, together with the atoms to which they are bound, are joined to form a heterocyclic, a substituted heterocyclic, a heteroaryl or substituted heteroaryl group optionally containing from 1 to 3 additional hetero ring atoms selected from the group consisting of oxygen, nitrogen and sulfur;
R4xe2x80x3 is selected from the group consisting of hydrogen and alkyl;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and xe2x80x94SO2R10 where R10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
R16 and R17 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; and
R18 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
R20 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
R21 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic;
b is 1 or 2;
and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
Preferably, the method employs a compound of formula IIId, IIIe or IIIf.
In another of its method aspects, this invention is directed to a method for treating a disease mediated by VLA-4 in a patient, which method comprises administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula IVa and/or IVb: 
wherein, in formula IVa, R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic;
in formula IVb, R1 and R2, together with the carbon atom and Wxe2x80x2 to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic;
and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula IVa or IVb is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where each R is independently hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, xe2x80x94N[S(O)xe2x80x94Rxe2x80x2]2 and xe2x80x94N[S(O)2xe2x80x94NRxe2x80x2]2 where each Rxe2x80x2 is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
R13 is selected from the group consisting of hydrogen, C1-10 alkyl, Cy, and Cy-C1-10 alkyl, wherein alkyl is optionally substituted with one to four substituents independently selected from Ra; and Cy is optionally substituted with one to four substituents independently selected from Rb;
R14 is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Cy, Cy-C1-10 alkyl, Cy-C2-10 alkenyl and Cy-C2-10 alkynyl, wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents selected from phenyl and Rx, and Cy is optionally substituted with one to four substituents independently selected from Ry;
or R13, R14 and the atoms to which they are attached together form a mono- or bicyclic ring containing 0-2 additional heteratoms selected from N, O and S;
R15 is selected from the group consisting of C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, aryl-C1-10 alkyl, heteroaryl, heteroaryl-C1-10 alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Rx, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Ry;
or R14, R15 and the carbon to which they are attached form a 3-7 membered mono- or bicyclic ring containing 0-2 heteroatoms selected from N, O and S;
Ra is selected from the group consisting of Cy and a group selected from Rx, wherein Cy is optionally substituted with one to four substituents independently selected from Rc;
Rb is selected from the group consisting of Ra, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl C1-10alkyl, heteroaryl C1-10 alkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from Rc;
Rc is selected from the group consisting of halogen, NO2, C(O)ORf, C1-4 alkyl, C1-4 alkoxy, aryl, aryl C1-4 alkyl, aryloxy, heteroaryl, NRfRg, RfC(O)Rg, NRfC(O)NRfRg, and CN;
Rd and Re are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Cy and Cy C1-10alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rc;
or Rd and Re together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
Rf and Rg are independently selected from hydrogen, C1-10 alkyl, Cy and Cy-C1-10 alkyl wherein Cy is optionally substituted with C1-10 alkyl; or Rf and Rg together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
Rh is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cyano, aryl, aryl C1-10 alkyl, heteroaryl, heteroaryl C1-10 alkyl, and xe2x80x94SO2Ri; wherein alkyl, alkenyl, and alkynl are optionally substituted with one to four substitutents independently selected from Ra; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from Rb;
Ri is selected from the group consisting of C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, and aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from Rc;
Rx is selected from the group consisting of xe2x80x94ORd, xe2x80x94NO2, halogen, xe2x80x94S(O)mRd, xe2x80x94SRd, xe2x80x94S(O)2Rd, xe2x80x94S(O)mNRdRe, xe2x80x94NRdRc, xe2x80x94O(CRfRg)nNRdRe, xe2x80x94C(O)Rd, xe2x80x94CO2Rd, xe2x80x94CO2(CRfRg)nCONRdRe, xe2x80x94OC(O)Rd, xe2x80x94CN, xe2x80x94C(O)NRdRe, xe2x80x94NRdC(O)Re, xe2x80x94OC(O)NRdRe, xe2x80x94NRdC(O)ORe, xe2x80x94NRdC(O)NRdRe, xe2x80x94CRd(Nxe2x80x94ORe), CF3, oxo, NRdC(O)NRdSO2Ri, NRdSO)mRe, xe2x80x94OS(O)2ORd, and xe2x80x94OP(O)(ORd)2;
Ry is selected from the group consisting of Rx, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl C1-10alkyl, heteroaryl C1-10 alkyl, cycloalkyl, heterocyclyl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substitutents independently selected from Rx;
Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;
m is an integer from 1 to 2;
n is an integer from 1 to 10;
W is selected from the group consisting of carbon and nitrogen;
Wxe2x80x2 is selected from the group consisting of carbon, nitrogen, oxygen, sulfur, S(O) and S(O)2;
Xxe2x80x2 is selected from the group consisting of xe2x80x94C(O)ORd, xe2x80x94P(O)(ORd)(ORe), xe2x80x94P(O)(Rd)(ORe), xe2x80x94S(O)mORd, xe2x80x94C(O)NRdRh, and -5-tetrazolyl;
and enantiomers, diastereomers and pharmaceutically acceptable salts thereof;
and further wherein the compound of formula IVa and/or IVb has a binding affinity to VLA-4 as expressed by an IC50 of about 15 xcexcM or less.
Preferably, in the above method, R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form a heteroaryl or substituted heteroaryl group having two nitrogen atoms in the heteroaryl ring. Optionally, the heteroaryl ring may contain other heteroatoms such as oxygen or sulfur. More preferably, R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form a pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring; more preferably, a pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen.
Preferably, Xxe2x80x2 is xe2x80x94C(O)ORd.
In a preferred embodiment, the above method employs a compound of formula Va, Vc, Vd, Ve or Vf: 
wherein R13, R14, R15 and Xxe2x80x2 are as defined herein;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and xe2x80x94SO2R10 where R10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl; and
R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
R16 and R17 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; and
R18 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
R20 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
R21 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic;
b is 1 or 2; and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.
More preferably, the above method employs a compound of formula Vd, Ve or Vf.
In yet another of its method aspects, this invention is directed to a method for treating a disease mediated by VLA-4 in a patient, which method comprises administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula VIa and/or VIb: 
wherein, in formula VIa, R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic;
in formula VIb, R1 and R2, together with the carbon atom and Wxe2x80x2 to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic;
and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula VIa or VIb is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where each R is independently hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, xe2x80x94N[S(O)xe2x80x94Rxe2x80x2]2 and xe2x80x94N[S(O)2xe2x80x94NRxe2x80x2]2 where each Rxe2x80x2 is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
R23 is selected from the group consisting of hydrogen, C1-10 alkyl optionally substituted with one to four substituents independently selected from Raxe2x80x2 and Cy optionally substituted with one to four substituents independently selected from Rbxe2x80x2;
R24 is selected from the group consisting of Arxe2x80x94Ar2xe2x80x94C1-10 alkyl, Ar1xe2x80x94Ar2xe2x80x94C2-10 alkenyl, Ar1xe2x80x94Ar2xe2x80x94C2-10 alkynyl, wherein Ar1 and Ar2 are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from Rbxe2x80x2; alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Raxe2x80x2;
R25 is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, aryl C1-10alkyl, heteroaryl, and heteroaryl C1-10 alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Raxe2x80x2, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rbxe2x80x2;
Raxe2x80x2 is selected from the group consisting of Cy, xe2x80x94ORdxe2x80x2, xe2x80x94NO2, halogen xe2x80x94S(O)mRdxe2x80x2, xe2x80x94SRdxe2x80x2, xe2x80x94S(O)2ORdxe2x80x2, xe2x80x94S(O)mNRdxe2x80x2Rexe2x80x2, xe2x80x94NRdxe2x80x2Rexe2x80x2, xe2x80x94O(CRfxe2x80x2Rgxe2x80x2)nNRdxe2x80x2Rcxe2x80x2, xe2x80x94C(O)Rdxe2x80x2, xe2x80x94CO2Rdxe2x80x2, xe2x80x94CO2(CRfxe2x80x2Rgxe2x80x2)nCONRdxe2x80x2Rexe2x80x2, xe2x80x94OC(O)Rdxe2x80x2, xe2x80x94CN, xe2x80x94C(O)NRdxe2x80x2Rexe2x80x2, xe2x80x94NRdxe2x80x2C(O)Rexe2x80x2, xe2x80x94OC(O)NRdxe2x80x2Rexe2x80x2, xe2x80x94NRdxe2x80x2C(O)ORexe2x80x2, xe2x80x94NRdxe2x80x2C(O)NRdxe2x80x2Rexe2x80x2, xe2x80x94CRdxe2x80x2(Nxe2x80x94ORexe2x80x2), CF3, and xe2x80x94OCF3;
wherein Cy is optionally substituted with one to four substituents independently selected from Rcxe2x80x2;
Rbxe2x80x2 is selected from the group consisting of Raxe2x80x2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl C1-10 alkyl, heteroaryl C1-10alkyl, wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from Rcxe2x80x2;
Rcxe2x80x2 is selected from the group consisting of halogen, amino, carboxy, C1-4 alkyl, C1-4 alkoxy, aryl, aryl C1-4 alkyl, hydroxy, CF3, and aryloxy;
Rdxe2x80x2 and Rcxe2x80x2 are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Cy and Cy C1-10alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rcxe2x80x2; or Rdxe2x80x2 and Rexe2x80x2 together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
Rfxe2x80x2 and Rgxe2x80x2 are independently selected from hydrogen, C1-10 alkyl, Cy and Cy-C1-10 alkyl; or Rfxe2x80x2 and Rgxe2x80x2 together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
Rhxe2x80x2 is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cyano, aryl, aryl C1-10 alkyl, heteroaryl, heteroaryl C1-10 alkyl, or xe2x80x94SO2Rixe2x80x2;
wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substitutents independently selected from Raxe2x80x2; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from Rbxe2x80x2;
Rixe2x80x2 is selected from the group consisting of C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, and aryl;
wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from Rcxe2x80x2;
Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;
Xxe2x80x3 is selected from the group consisting of xe2x80x94C(O)ORdxe2x80x2, xe2x80x94P(O)(ORdxe2x80x2)(ORexe2x80x2), xe2x80x94P(O)(Rdxe2x80x2)(ORexe2x80x2), xe2x80x94S(O)mORdxe2x80x2, xe2x80x94C(O)NRdxe2x80x2Rhxe2x80x2, and -5-tetrazolyl;
m is an integer from 1 to 2;
n is an integer from 1 to 10;
and enantiomers, diastereomers and pharmaceutically acceptable salts thereof;
and further wherein the compound of formula VIa and/or VIb has a binding affinity to VLA-4 as expressed by an IC50 of about 15 xcexcM or less.
Preferably, in the above method, R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form a heteroaryl or substituted heteroaryl group having two nitrogen atoms in the heteroaryl ring. Optionally, the heteroaryl ring may contain other heteroatoms such as oxygen or sulfur. More preferably, R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form a pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring; more preferably, a pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine, pyrazine, 1-oxo-1,2.5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen.
Preferably, in the above method, Xxe2x80x3 is xe2x80x94C(O)ORdxe2x80x2.
Preferably, R24 is xe2x80x94CH2xe2x80x94Ar2xe2x80x94Ar1 and R25 is hydrogen.
In a preferred embodiment, the above method employs a compound of formula VIIa, VIIc, VIId, VIIe or VIIf: 
wherein R23, R24, R25 and Xxe2x80x3 are as defined herein;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and xe2x80x94SO2R10 where R10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl; and
R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
R16 and R17 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; and
R18 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
R20 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
R21 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic;
b is 1 or 2;
and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
Preferably, the compound employed in the above method is selected from formula VIId, VIIe or VIIf.
The compounds and pharmaceutical compositions of this invention are useful for treating disease conditions mediated by VLA-4 or leucocyte adhesion. Such disease conditions include, by way of example, asthma, Alzheimer""s disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn""s disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
Other disease conditions include, but are not limited to, inflammatory conditions such as erythema nodosum, allergic conjunctivitis, optic neuritis, uveitis, allergic rhinitis, Ankylosing spondylitis, psoriatic arthritis, vasculitis, Reiter""s syndrome, systemic lupus erythematosus, progressive systemic sclerosis, polymyositis, dermatomyositis, Wegner""s granulomatosis, aortitis, sarcoidosis, lymphocytopenia, temporal arteritis, pericarditis, myocarditis, congestive heart failure, polyarteritis nodosa, hypersensitivity syndromes, allergy, hypereosinophilic syndromes, Churg-Strauss syndrome, chronic obstructive pulmonary disease, hypersensitivity pneumonitis, chronic active hepatitis, interstitial cystitis, autoimmune endocrine failure, primary biliary cirrhosis, autoimmune aplastic anemia, chronic persistent hepatitis and thyroiditis.
In a preferred embodiment, the disease condition mediated by VLA-4 is an inflammatory disease.
The present invention is also directed to novel compounds useful for treating a disease condition mediated by VLA-4 or leucocyte adhesion. Accordingly, in one of its composition aspects, this invention is directed to a compound of formula Ia and/or Ib: 
wherein, in formula Ia, R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic;
in formula Ib, R1 and R2, together with the carbon atom and Wxe2x80x2 to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic;
and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula Ia or Ib is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where each R is independently hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, xe2x80x94N[S(O)xe2x80x94Rxe2x80x2]2 and xe2x80x94N[S(O)2xe2x80x94NRxe2x80x2]2 where each Rxe2x80x2 is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
R3 is xe2x80x94(CH2)xxe2x80x94Arxe2x80x94R9, where Ar is aryl, substituted aryl, heteroaryl and substituted heteroaryl; R9 is selected from the group consisting of acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, oxythiocarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl; x is an integer from 0 to 4;
R3xe2x80x2 is selected from the group consisting of hydrogen, isopropyl, xe2x80x94CH2Z where Z is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
Q is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2, and xe2x80x94NR4xe2x80x94;
R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic or, optionally, R4 and R1 or R4 and R2, together with the atoms to which they are bound, are joined to form a heteroaryl, a substituted heteroaryl, a heterocyclic or a substituted heterocyclic group;
W is selected from the group consisting of nitrogen and carbon; and
Wxe2x80x2 is selected from the group consisting of nitrogen, carbon, oxygen, sulfur, S(O), and S(O)2;
X is selected from the group consisting of hydroxyl, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy and xe2x80x94NRxe2x80x3Rxe2x80x3 where each Rxe2x80x3 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
and enantiomers, diasteromers and pharmaceutically acceptable salts thereof;
and further wherein the compound of formula Ia and/or Ib has a binding affinity to VLA-4 as expressed by an IC50 of about 15 xcexcM or less.
More preferably, R3 is a group of the formula: 
wherein R9 and x are as defined herein. Preferably, R9 is in the para position of the phenyl ring; and x is an integer of from 1 to 4, more preferably, x is 1.
Preferably, R3xe2x80x2 is hydrogen.
In a preferred embodiment, R9 is selected from the group consisting of xe2x80x94Oxe2x80x94Zxe2x80x94NR11R11xe2x80x2 and xe2x80x94Oxe2x80x94Zxe2x80x94R12 wherein R11 and R11xe2x80x2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, and where R11 and R11xe2x80x2 are joined to form a heterocycle or a substituted heterocycle, R12 is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of xe2x80x94C(O)xe2x80x94 and xe2x80x94SO2xe2x80x94. More preferably, R9 is xe2x80x94OC(O)NR11R11xe2x80x2, wherein R11 and R11xe2x80x2 are as defined herein.
Preferably, in the above compounds, Z is xe2x80x94C(O)xe2x80x94 and Q is preferably xe2x80x94NR4.
In a preferred embodiment, this invention is directed to compounds of formula IIa or IIb: 
wherein X is as defined herein;
R3 is xe2x80x94(CH2)xxe2x80x94Arxe2x80x94R9, where Ar is aryl, substituted aryl, heteroaryl and substituted heteroaryl; R9 is selected from the group consisting of acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, oxythiocarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl; x is an integer from 0 to 4;
R3xe2x80x2 is selected from the group consisting of hydrogen, isopropyl, xe2x80x94CH2Z where Z is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
ring A and ring B independently form a heteroaryl or substituted heteroaryl group having two nitrogen atoms in the heteroaryl ring;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and xe2x80x94SO2R10 where R10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
or optionally, one of, R4 and ring A, R4 and R5, R4 and R6, or R5 and R6, together with the atoms to which they are bound, can be joined to form a heterocyclic or substituted heterocyclic ring;
and enantiomers, diastereomers and pharmaceutically acceptable salts thereof; and provided that ring B does not form a 6-amino or substituted amino pyrimidin-4-yl group.
R3xe2x80x2 is preferably hydrogen. Preferably, x is an integer from 1 to 4; more preferably, x is 1.
Preferably, ring A forms a pyridazine, pyrimidine or pyrazine ring; more preferably, a pyrimidine or pyrazine ring; wherein the pyridazine, pyrimidine or pyrazine ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen.
Preferably, ring B forms a pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or a 1,1-dioxo-1,2,5-thiadiazole ring; more preferably, a pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or a 1,1-dioxo-1,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine or pyrazine ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen.
In another preferred embodiment, this invention is directed to compounds of formula IIIa, IIIc, IIId, IIIe or IIIf: 
wherein X is as defined herein;
R3 is xe2x80x94(CH2)xxe2x80x94Arxe2x80x94R9, where Ar is aryl, substituted aryl, heteroaryl and substituted heteroaryl; R9 is selected from the group consisting of acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, oxythiocarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl; x is an integer from 0 to 4;
R3xe2x80x2 is selected from the group consisting of hydrogen, isopropyl, xe2x80x94CH2Z where Z is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
R4xe2x80x2 is selected from the group consisting of hydrogen and alkyl or, optionally, one of, R4xe2x80x2 and R5, R4xe2x80x2 and R6, R5 and R6, R5 and R8, or R6 and R8, together with the atoms to which they are bound, are joined to form a heterocyclic, a substituted heterocyclic, a heteroaryl or substituted heteroaryl group optionally containing from 1 to 3 additional hetero ring atoms selected from the group consisting of oxygen, nitrogen and sulfur;
R4xe2x80x3 is selected from the group consisting of hydrogen and alkyl;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and xe2x80x94SO2R10 where R10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
R16 and R17 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; and
R18 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
R20 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
R21 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic;
b is 1 or 2;
and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
In the above compounds, R3xe2x80x2 is preferably hydrogen. Preferably, x is an integer from 1 to 4; more preferably, x is 1.
Preferably, the compound is selected from formula IIId, IIIe or IIIf.
In another of its composition aspects, this invention is directed to a compound of formula IVa: 
wherein R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form a heteroaryl group having two nitrogen atoms in the heteroaryl ring;
and further wherein said heteroaryl group is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where each R is independently hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, xe2x80x94N[S(O)2xe2x80x94Rxe2x80x2]2 and xe2x80x94N[S(O)2xe2x80x94NRxe2x80x2]2 where each Rxe2x80x2 is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
R13 is selected from the group consisting of hydrogen, C1-10 alkyl, Cy, and Cy-C1-10 alkyl, wherein alkyl is optionally substituted with one to four substituents independently selected from Raxe2x80x2; and Cy is optionally substituted with one to four substituents independently selected from Rb;
R14 is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Cy, Cy-C1-10 alkyl, Cy-C2-10 alkenyl and Cy-C2-10 alkynyl, wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents selected from phenyl and RX, and Cy is optionally substituted with one to four substituents independently selected from Ry;
or R13, R14 and the atoms to which they are attached together form a mono- or bicyclic ring containing 0-2 additional heteratoms selected from N, O and S,
R15 is selected from the group consisting of C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, aryl-C1-10 alkyl, heteroaryl, heteroaryl-C1-10 alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Rx, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Ry;
or R14, R15 and the carbon to which they are attached form a 3-7 membered mono- or bicyclic ring containing 0-2 heteroatoms selected from N, O and S;
Ra is selected from the group consisting of Cy and a group selected from Rx, wherein Cy is optionally substituted with one to four substituents independently selected from Rc;
Rb is selected from the group consisting of Ra, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl C1-10 alkyl, heteroaryl C1-10 alkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from Rc;
Rc is selected from the group consisting of halogen, NO2, C(O)ORf, C1-4 alkyl, C1-4 alkoxy, aryl, aryl C1-4 alkyl, aryloxy, heteroaryl, NRfRg, RfC(O)Rg, NRf(O)NRfRg, and CN;
Rd and Re are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Cy and Cy C1-10alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rc;
or Rd and Re together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
Rf and Rg are independently selected from hydrogen, C1-10 alkyl, Cy and Cy-C1-10 alkyl wherein Cy is optionally substituted with C1-10 alkyl; or Rf and Rg together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
Rh is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cyano, aryl, aryl C1-10 alkyl, heteroaryl, heteroaryl C1-10 alkyl, and xe2x80x94SO2Ri; wherein alkyl, alkenyl, and alkynl are optionally substituted with one to four substitutents independently selected from Ra; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from Rb;
Ri is selected from the group consisting of C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, and aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from Rc;
Rx is selected from the group consisting of xe2x80x94ORd, xe2x80x94NO2, halogen, xe2x80x94S(O)mRd, xe2x80x94SRd, xe2x80x94S(O)2ORd, xe2x80x94S(O)mNRdRe, xe2x80x94NRdRc, xe2x80x94O(CRfRg)nNRdRe, xe2x80x94C(O)Rd, xe2x80x94CO2Rd, xe2x80x94CO2(CRfRg)nCONRdRe, xe2x80x94OC(O)Rd, xe2x80x94CN, xe2x80x94C(O)NRdRe, xe2x80x94NRdC(O)Rc, xe2x80x94OC(O)NRdRc, xe2x80x94NRdC(O)ORe, xe2x80x94NRdC(O)NRdRc, xe2x80x94CRd(Nxe2x80x94ORc), CF3, oxo, NRdC(O)NRdSO2Ri, NRdS(O)mRe, xe2x80x94OS(O)2ORd, and xe2x80x94OP(O)(OR)d)2;
Ry is selected from the group consisting of Rx, C2-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, C1-10alkyl, heteroaryl C1-10 alkyl, cycloalkyl, heterocyclyl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four subtitutents independently selected from Rx;
Cy is cycloakyl, heterocyclyl, aryl, or hetoaryl;
m is an integer from 1 to 2;
n is an integer from 1 to 10;
W is selected from the group consisting of carbon and nitrogen;
Wxe2x80x2 is selected from the group consisting of carbon, nitrogen, oxygen, sulfur, S(O) and S(O)2;
Xxe2x80x2 is selected from the group consisting of xe2x80x94C(O)ORd, xe2x80x94P(O)(ORd)(ORe), xe2x80x94P(O)(Rd)(ORe), xe2x80x94S(O)mORd, xe2x80x94C(O)NRdRh, -5-tetrazoyl;
and enantiomers, diastereomers and pharmaceutically acceptable salts thereof;
and further wherein the compound of formula IV has a binding affinity to VLA-4 as expressed by an IC50 of about 15 xcexcM less
and provided that when R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form a 2-arylpyrimidin-4-yl group and R14 is hydrogen, then R15 is not alkyl of from 1 to 6 carbon atoms optionally substituted with hydroxyl; and when R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form a 5-arylpyrazin-2-yl group and R14 is hydrogen, then R15 is not 4-hydroxybenzyl.
In the above compounds, R1 and R2 are preferably joined to form an pyradazine, pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring; more preferably, a pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen.
Preferably, in the above compounds, Xxe2x80x2 is xe2x80x94C(O)ORd.
In a preferred embodiment, this invention is directed to compounds of of formula Va, Vc, Vd, Ve or Vf: 
wherein R13, R 14 R15 and Xxe2x80x2 are as defined herein;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and xe2x80x94SO2R10 where R10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl; and
R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
R16 and R17 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; and
R18 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
R20is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
R21 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic;
b is 1 or 2;
and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
More preferably, the compound is selected from formula Vd, Ve or Vf.
In yet another of its composition aspects, this invention is directed to a compound of formula VIa and/or VIb: 
wherein, in formula VIa, R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic;
in formula VIb, R1 and R2, together with the carbon atom and Wxe2x80x2 to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic;
and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula VIa or VIb is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where each R is independently hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O),-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, xe2x80x94N[S(O)2xe2x80x94Rxe2x80x2]2 and xe2x80x94N[S(O)2xe2x80x94NRxe2x80x2]2 where each Rxe2x80x2 is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
R23 is selected from the group consisting of hydrogen, C1-10 alkyl optionally substituted with one to four substituents independently selected from Raxe2x80x2 and Cy optionally substituted with one to four substituents independently selected from Rbxe2x80x2;
R24 is selected from the group consisting of Ar1xe2x80x94Ar2xe2x80x94C1-10 alkyl, Ar1xe2x80x94Ar2xe2x80x94C2xe2x80x94C2-10 alkenyl, Ar1xe2x80x94Ar2xe2x80x94C2-10 alkynyl, wherein Ar1 and Ar2 are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from Rbxe2x80x2; alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Raxe2x80x2;
R25 is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, aryl C1-10alkyl, heteroaryl, and heteroaryl C1-10 alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Raxe2x80x2, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rbxe2x80x2;
Raxe2x80x2 is selected from the group consisting of Cy, xe2x80x94ORdxe2x80x2, xe2x80x94NO2, halogen xe2x80x94S(O)mRdxe2x80x2, SRdxe2x80x2, xe2x80x94S(O)2ORdxe2x80x2, xe2x80x94S(O)mNRdxe2x80x2Rexe2x80x2, xe2x80x94NRdxe2x80x2Rcxe2x80x2, xe2x80x94O(CRfxe2x80x2Rgxe2x80x2)nNRdxe2x80x2Rexe2x80x2, xe2x80x94C(O)Rdxe2x80x2, xe2x80x94CO2Rdxe2x80x2, xe2x80x94CO2(CRfxe2x80x2Rgxe2x80x2)nCONRdxe2x80x2Rexe2x80x2, xe2x80x94OC(O)Rdxe2x80x2, xe2x80x94CN, xe2x80x94C(O)NRdxe2x80x2Rexe2x80x2, xe2x80x94NRdxe2x80x2C(O)Rexe2x80x2, xe2x80x94OC(O)NRdxe2x80x2Rexe2x80x2, xe2x80x94NRdxe2x80x2C(O)ORexe2x80x2, xe2x80x94Nrdxe2x80x2C(O)NRdxe2x80x2Rexe2x80x2, xe2x80x94CRdxe2x80x2(Nxe2x80x94ORexe2x80x2), CF3, and xe2x80x94OCF3;
wherein Cy is optionally substituted with one to four substituents independently selected from Rcxe2x80x2;
Rbxe2x80x2 is selected from the group consisting of Raxe2x80x2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl C2-10 alkyl, heteroaryl C1-10 alkyl,
wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from Rcxe2x80x2;
RCxe2x80x2 is selected from the group consisting of halogen, amino, carboxy, C1-4 alkyl, C1-4 alkoxy, aryl, aryl C1-4 alkyl, hydroxy, CF3, and aryloxy;
Rdxe2x80x2 and Rexe2x80x2 are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Cy and Cy C1-10alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rcxe2x80x2; or Rdxe2x80x2 and R together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
Rfxe2x80x2 and Rgxe2x80x2are independently selected from hydrogen, C1-10 alkyl, Cy and Cy-C1-10 alkyl; or Rfxe2x80x2 and Rgxe2x80x2 together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
Rhxe2x80x2 is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cyano, aryl, aryl C1-10 alkyl, heteroaryl, heteroaryl C1-10 alkyl, or xe2x80x94SO2Rixe2x80x2;
wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substitutents independently selected from Raxe2x80x2; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from Rbxe2x80x2;
Rixe2x80x2 is selected from the group consisting of C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, and aryl;
wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from Rcxe2x80x2;
Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;
Xxe2x80x3 is selected from the group consisting of xe2x80x94C(O)ORdxe2x80x2, xe2x80x94P(O)(ORdxe2x80x2)(ORexe2x80x2), xe2x80x94P(O)(Rdxe2x80x2 )(ORexe2x80x2), xe2x80x94S(O)mORdxe2x80x2, xe2x80x94C(O)NRdxe2x80x2Rhxe2x80x2, and -5-tetrazolyl;
m is an integer from 1 to 2;
n is an integer from 1 to 10;
and enantiomers, diastereomers and pharmaceutically acceptable salts thereof;
and further wherein the compounds of-formula VIa and/or VIb have a binding affinity to VLA-4 as expressed by an IC50 of about 15 xcexcM or less.
In the above compounds, R1 and R2 are preferably joined to form a heteroaryl or substituted heteroaryl group having two nitrogen atoms in the heteroaryl ring. More preferably, R1 and R2 are joined to form a pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring; more preferably, a pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen.
Preferably, Xxe2x80x3 is xe2x80x94C(O)ORdxe2x80x2.
In the above compounds, R24 is preferably xe2x80x94CH2xe2x80x94Ar2xe2x80x94r1 and R25 is preferably hydrogen.
In a preferred embodiment, this invention is directed to compounds of formula VIIa, VIIc, VId, VIIe or VIIf: 
wherein R24, R25 and Xxe2x80x3 are as defined herein;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and xe2x80x94SO2R10 where R10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl; and
R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
R16 and R17 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; and
R18 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
R20 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
R21 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic;
b is 1 or 2;
and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
Preferably, the compound is selected from formula VIId, VIIe or VIIf.
This invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compounds defined herein.
In the above compounds, when X is other than xe2x80x94OH or pharmaceutical salts thereof, X is preferably a substituent which will convert (e.g., hydrolyze, metabolize, etc.) in vivo to a compound where X is xe2x80x94OH or a salt thereof. Accordingly, suitable X groups are any art recognized pharmaceutically acceptable groups which will hydrolyze or otherwise convert in vivo to a hydroxyl group or a salt thereof including, by way of example, esters (X is alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, alkenoxy, substituted alkenoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclooxy, substituted heterocyclooxy, and the like).
Unless otherwise defined, R3 and R15 in the above compounds are preferably selected from all possible isomers arising by substitution with the following groups:
4-methylbenzyl,
4-hydroxybenzyl,
4-methoxybenzyl,
4-t-butoxybenzyl,
4-benzyloxybenzyl,
4-[xcfx86xe2x80x94CH(CH3)Oxe2x80x94]benzyl,
4-[xcfx86xe2x80x94CH(COOH)Oxe2x80x94]benzyl,
4-[BocNHCH2C(O)NHxe2x80x94]benzyl,
4-chlorobenzyl,
4-[NH2CH2C(O)NHxe2x80x94]benzyl,
4-carboxybenzyl,
4-[CbzNHCH2CH2NHxe2x80x94]benzyl,
3-hydroxy4xe2x80x94(xcfx86xe2x80x94OC(O)NHxe2x80x94)benzyl,
4-[HOOCCH2CH2C(O)NHxe2x80x94]benzyl,
benzyl,
4-[2xe2x80x2-carboxylphenoxy-]benzyl,
4-[xcfx86xe2x80x94C(O)NHxe2x80x94]benzyl,
3-carboxybenzyl,
4-iodobenzyl,
4-hydroxy-3,5-diiodobenzyl,
4-hydroxy-3-iodobenzyl,
4-[2xe2x80x2-carboxyphenyl-]benzyl,
xcfx86xe2x80x94CH2CH2xe2x80x94,
4-nitrobenzyl,
2-carboxybenzyl,
4-[dibenzylamino]-benzyl,
4-[(1xe2x80x2-cyclopropylpiperidin-4xe2x80x2-yl)C(O)NHxe2x80x94]benzyl,
4-[xe2x80x94NHC(O)CH2NHBoc]benzyl,
4-carboxybenzyl,
4-hydroxy-3-nitrobenzyl,
4-[xe2x80x94NHC(O)CH(CH3)NHBoc]benzyl,
4-[xe2x80x94NHC(O)CH(CH2xcfx86)NHBoc]benzyl,
isobutyl,
methyl,
4-[CH3C(O)NHxe2x80x94]benzyl,
xe2x80x94CH2xe2x80x94(3-indolyl),
n-butyl,
t-butylxe2x80x94OC(O)CH2xe2x80x94,
t-butylxe2x80x94OC(O)CH2CH2xe2x80x94,
H2NC(O)CH2xe2x80x94,
H2NC(O)CH2CH2xe2x80x94,
BocNHxe2x80x94(CH2)4xe2x80x94,
t-butylxe2x80x94OC(O)xe2x80x94(CH2)2xe2x80x94,
HOOCCH2xe2x80x94,
HOOC(CH2)2xe2x80x94,
H2N(CH2)4xe2x80x94,
isopropyl,
(1-naphthyl)xe2x80x94CH2xe2x80x94,
2xe2x80x94(2-naphthyl)xe2x80x94CH2xe2x80x94,
(2-th iophenyl)xe2x80x94CH2xe2x80x94,
(xcfx86xe2x80x94CH2xe2x80x94OC(O)NHxe2x80x94(CH2)4xe2x80x94,
cyclohexylxe2x80x94CH2xe2x80x94,
benzyloxyxe2x80x94CH2xe2x80x94,
HOCH2xe2x80x94,
5xe2x80x94(3xe2x80x94N-benzyl)imidazolylxe2x80x94CH2xe2x80x94,
2-pyridylxe2x80x94CH2xe2x80x94,
3-pyridylxe2x80x94CH2xe2x80x94,
4-pyridylxe2x80x94CH2xe2x80x94,
5xe2x80x94(3-N-methyl)imidazolylxe2x80x94CH2xe2x80x94,
N-benzylpiperid-4-ylxe2x80x94CH2xe2x80x94,
N-Boc-piperidin-4-ylxe2x80x94CH2xe2x80x94,
Nxe2x80x94(phenyl-carbonyl)piperidin-4-ylxe2x80x94CH2xe2x80x94,
H3CSCH2CH2xe2x80x94,
1-N-benzylimidazol-4-yl-CH2xe2x80x94,
iso-propylxe2x80x94C(O)NHxe2x80x94(CH2)4xe2x80x94,
iso-butylxe2x80x94C(O)NHxe2x80x94(CH2)4xe2x80x94,
phenylxe2x80x94C(O)NHxe2x80x94(CH2)4xe2x80x94,
benzylxe2x80x94C(O)NHxe2x80x94(CH2)4xe2x80x94,
allylxe2x80x94C(O)NHxe2x80x94(CH2)4xe2x80x94,
4xe2x80x94(3-N-methylimidazolyl)xe2x80x94CH2xe2x80x94,
4-imidazolyl,
4-[(CH3)2NCH2CH2CH2xe2x80x94Oxe2x80x94]benzyl,
4-[(benzyl)2N-]-benzyl,
4-aminobenzyl,
allyloxyxe2x80x94C(O)NH(CH2)4xe2x80x94,
allyloxyxe2x80x94C(O)NH(CH2)3xe2x80x94,
allyloxyxe2x80x94C(O)NH(CH2)2xe2x80x94,
NH2C(O)CH2xe2x80x94,
xcfx86xe2x80x94CHxe2x95x90,
2-pyridylxe2x80x94C(O)NHxe2x80x94(CH2)4xe2x80x94,
4-methylpyrid-3-ylxe2x80x94C(O)NHxe2x80x94(CH2)4xe2x80x94,
3-methylthien-2-ylxe2x80x94C(O)NHxe2x80x94(CH2)4xe2x80x94,
2-pyrrolylxe2x80x94C(O)NHxe2x80x94(CH2)4xe2x80x94,
2-furanylxe2x80x94C(O)NHxe2x80x94(CH2)4xe2x80x94,
4-methylphenylxe2x80x94SO2xe2x80x94N(CH3)CH2C(O)NH(CH2)4xe2x80x94,
4-[cyclopentylacetylenyl]-benzyl,
4-[xe2x80x94NHC(O)xe2x80x94(N-Boc)-pyrrolidin-2-yl)]-benzyl-,
1 -N-methylimidazol-4-ylxe2x80x94CH2xe2x80x94,
1 -N-methylimidazol-5-ylxe2x80x94CH2xe2x80x94,
imidazol-5-ylxe2x80x94CH2xe2x80x94,
6-methylpyrid-3-ylxe2x80x94C(O)NHxe2x80x94(CH2)4xe2x80x94,
4-[2xe2x80x2-carboxymethylphenyl]-benzyl,
4-[xe2x80x94NHC(O)NHCH2CH2CH2xe2x80x94xcfx86]-benzyl,
4-[xe2x80x94NHC(O)NHCH2CH2xe2x80x94xcfx86]-benzyl,
xe2x80x94CH2C(O)NH(CH2)4xcfx86,
4-[xcfx86(CH2)4O-]-benzyl,
4-[xe2x80x94Cxe2x89xa1Cxe2x80x94xcfx86-4xe2x80x2xcfx86]-benzyl,
4-[xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94Oxe2x80x94S(O)2-4xe2x80x2-CH3xe2x80x94xcfx86]-benzyl,
4-[xe2x80x94Cxe2x89xa1Cxe2x80x94CH2NHC(O)NH2]-benzyl,
4-[xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94O-4xe2x80x2-COOCH2CH3xe2x80x94xcfx86]-benzyl,
4-[xe2x80x94Cxe2x89xa1Cxe2x80x94CH(NH2)-cyclohexyl]-benzyl,
xe2x80x94(CH2)4NHC(O)CH2-3-indolyl,
xe2x80x94(CH2)4NHC(O)CH2CH2-3-indolyl,
xe2x80x94(CH2)4NHC(O)-3xe2x80x94(5-methoxyindolyt),
xe2x80x94(CH2)4NHC(O)-3xe2x80x94(1 -methylindolyl),
xe2x80x94(CH2)4NHC(O)-4xe2x80x94(xe2x80x94SO2(CH3)xe2x80x94xcfx86),
xe2x80x94(CH2)4NHC(O)-4xe2x80x94(C(O)CH3)-phenyl,
xe2x80x94(CH2)4NHC(O)-4-fluorophenyl,
xe2x80x94(CH2)4NHC(O)CH2O-4-fluorophenyl,
4-[xe2x80x94Cxe2x89xa1Cxe2x80x94(2-pyridyl)]benzyl,
4-[xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94O-phenyl]benzyl,
4-[xe2x80x94Cxe2x89xa1Cxe2x80x94CH2OCH3]benzyl,
4-[xe2x80x94Cxe2x89xa1Cxe2x80x94(3-hydroxyphenyl)]benzyl,
4-[xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94O-4xe2x80x2xe2x80x94(xe2x80x94C(O)OC2H5)phenyl]benzyl,
4-[xe2x80x94Cxe2x89xa1Cxe2x80x94CH2CH(C(O)OCH3)2]benzyl,
4-[xe2x80x94Cxe2x89xa1Cxe2x80x94CH2NHxe2x80x94(4,5-dihydro4-oxo-5-phenyl-oxazol-2-yl),
3-aminobenzyl,
4-[xe2x80x94Cxe2x89xa1Cxe2x80x94CH2CH(NHC(O)CH3)C(O)OH]-benzyl,
xe2x80x94CH2C(O)NHCH(CH3)xcfx86,
xe2x80x94CH2C(O)NHCH2xe2x80x94(4-dimethylamino)-xcfx86,
xe2x80x94CH2C(O)NHCH2xe2x80x944-nitrophenyl,
xe2x80x94CH2CH2C(O)N(CH3)CH2xe2x80x94xcfx86,
xe2x80x94CH2CH2C(O)NHCH2CH2xe2x80x94(N-methyl)-2-pyrrolyl,
xe2x80x94CH2CH2C(O)NHCH2CH2CH2CH3,
xe2x80x94CH2CH2C(O)NHCH2CH2-3-indolyl,
xe2x80x94CH2C(O)N(CH3)CH2phenyl,
xe2x80x94CH2C(O)NH(CH2)2xe2x80x94(N-methyl)-2-pyrrolyl,
xe2x80x94CH2C(O)NHCH2CH2CH2CH3,
xe2x80x94CH2C(O)NHCH2CH2-3-indolyl,
xe2x80x94(CH2)2C(O)NHCH(CH3)xcfx86,
xe2x80x94(CH2)2C(O)NHCH2-4-dimethylaminophenyl,
xe2x80x94(CH2)2C(O)NHCH2-4-nitrophenyl,
xe2x80x94CH2C(O)NH-4-[xe2x80x94NHC(O)CH3-phenyl],
xe2x80x94CH2C(O)NH-4-pyridyl,
xe2x80x94CH2C(O)NH-4-[dimethylaminophenyl],
xe2x80x94CH2C(O)NH-3-methoxyphenyl,
xe2x80x94CH2CH2C(O)NH-4-chlorophenyl,
xe2x80x94CH2CH2C(O)NH-2-pyridyl,
xe2x80x94CH2CH2C(O)NH-4-methoxyphenyl,
xe2x80x94CH2CH2C(O)NH-3-pyridyl,
4-[(CH3)2NCH2CH2Oxe2x80x94]benzyl,
xe2x80x94(CH2)3NHC(NH)NHxe2x80x94SO2-4-methylphenyl,
4-[(CH3)2NCH2CH2Oxe2x80x94]benzyl,
xe2x80x94(CH2)4NHC(O)NHCH2CH3,
xe2x80x94(CH2)4NHC(O)NH-phenyl,
xe2x80x94(CH2)4NHC(O)NH-4-methoxyphenyl,
4-[4xe2x80x2-pyridyl-C(O)NHxc3x97]benzyl,
4-[3xe2x80x2-pyridyl-C(O)NHxc3x97]benzyl,
4-[xe2x80x94NHC(O)NH-3xe2x80x2-methylphenyl]benzyl,
4-[xe2x80x94NHC(O)CH2NHC(O)NH-3xe2x80x2-methylphenyl]benzyl,
4-[xe2x80x94NHC(O)xe2x80x94(2xe2x80x2,3xe2x80x2-dihydroindol-2-yl)]benzyl,
4-[xe2x80x94NHC(O)xe2x80x94(2xe2x80x2,3xe2x80x2-dihydro-N-Boc-indol-2-yl)]benzyl,
p-[xe2x80x94OCH2CH2-1xe2x80x2xe2x80x94(4xe2x80x2-pyrimidinyl)-piperazinyl]benzyl,
4-[xe2x80x94OCH2CH2xe2x80x94(1xe2x80x2-piperidinyl]benzyl,
4-[xe2x80x94OCH2CH2xe2x80x94(1xe2x80x2-pyrrolidinyl)]benzyl,
4-[xe2x80x94OCH2CH2CH2xe2x80x94(1xe2x80x2-piperidinyl)]benzyl-,
xe2x80x94CH2-3xe2x80x94(1,2,4-triazolyl),
4-[xe2x80x94OCH2CH2CH2-4xe2x80x94(3xe2x80x2-chlorophenyl)-piperazin-1-yl]benzyl,
4-[xe2x80x94OCH2CH2N(xcfx86)CH2CH3]benzyl,
4-[xe2x80x94OCH2-3xe2x80x2xe2x80x94(N-Boc)-piperidinyl]benzyl,
4-[di-n-pentylamino]benzyl,
4-[n-pentylamino]benzyl,
4-[di-iso-propylaminoxe2x80x94CH2CH2Oxe2x80x94]benzyl,
4-[xe2x80x94OCH2CH2xe2x80x94(N-morpholinyl)]benzyl,
4-[xe2x80x94Oxe2x80x94(3xe2x80x2xe2x80x94(N-Boc)-piperidinyl]benzyl,
4-[xe2x80x94OCH2CH(NHBoc)CH2cyclohexyl]benzyl,
p-[OCH2Ch2xe2x80x94(N-piperidinyl]benzyl,
4-[xe2x80x94OCH2CH2CH2xe2x80x94(4-m-chlorophenyl)-piperazin-1-yl]benzyl,
4-[xe2x80x94OCH2CH2xe2x80x94(N-homopiperidinyl)benzyl,
4-[xe2x80x94NHC(O)-3xe2x80x2xe2x80x94(N-Boc)-piperidinyl]benzyl,
4-[xe2x80x94OCH2CH2N(benzyl)2]benzyl,
xe2x80x94CH2-2-thiazolyl,
3-hydroxybenzyl,
4-[xe2x80x94OCH2CH2CH2N(CH3)2]benzyl,
4-[xe2x80x94NHC(S)NHCH2CH2xe2x80x94(N-morpholino)]benzyl,
4-[xe2x80x94OCH2CH2N(C2H5)2]benzyl,
4-[xe2x80x94OCH2CH2CH2N(C2H5)2]benzyl,
4-[CH3(CH2)4NHxe2x80x94]benzyl,
4-[N-n-butyl,N-n-pentylamino-]benzyl,
4-[xe2x80x94NHC(O)-4xe2x80x2-piperidinyl]benzyl,
4-[xe2x80x94NHC(O)CH(NHBoc)(CH2)4NHCbz]benzyl,
4-[xe2x80x94NHC(O)xe2x80x94(1xe2x80x2,2xe2x80x2,3xe2x80x2, 4xe2x80x2-tetrahydro-N-Boc-isoquinolin-1xe2x80x2-yl]benzyl,
p-[xe2x80x94OCH2CH2CH2-1xe2x80x2xe2x80x94(4xe2x80x2-methyl)-piperazinyl]benzyl,
xe2x80x94(CH2)4NH-Boc,
3-[xe2x80x94OCH2CH2CH2N(CH3)2]benzyl,
4-[xe2x80x94OCH2CH2CH2N(CH3)2]benzyl,
3-[xe2x80x94OCH2CH2xe2x80x94(1xe2x80x2-pyrrolidinyl)]benzyl,
4-[xe2x80x94OCH2CH2CH2N(CH3)benzyl]benzyl,
4-[xe2x80x94NHC(S)NHCH2CH2Ch2xe2x80x94(N-morpholino)]benzyl,
4-[xe2x80x94OCH2CH2xe2x80x94(N-morpholino)]benzyl,
4-[xe2x80x94NHCH2xe2x80x94(4xe2x80x2-chlorophenyl)]benzyl,
4-[xe2x80x94NHC(O)NHxe2x80x94(4xe2x80x2-cyanophenyl)]benzyl,
4-[xe2x80x94OCH2COOH]benzyl,
4-[xe2x80x94OCH2COO-t-butyl]benzyl,
4-[xe2x80x94NHC(O)-5xe2x80x2-fluoroindol-2-yl]benzyl,
4-[xe2x80x94NHC(S)NH(CH2)2-1-piperidinyl]benzyl,
4-[xe2x80x94N(SO2CH3)(CH2)3-N(CH3)2]benzyl,
4-[xe2x80x94NHC(O)CH2CH(C(O)OCH2xcfx86)xe2x80x94NHCbz]benzyl,
4-[xe2x80x94NHS(O)2CF3]benzyl,
3-[xe2x80x94Oxe2x80x94(N-methylpiperidin-4xe2x80x2-yl]benzyl,
4-[xe2x80x94C(xe2x95x90NH)NH2]benzyl,
4-[xe2x80x94NHSO2xe2x80x94CH2Cl]benzyl,
4-[xe2x80x94NHC(O)xe2x80x94(1xe2x80x2,2xe2x80x2,3xe2x80x2, 4xe2x80x2-tetrahydroisoquinolin-2xe2x80x2-yl]benzyl,
4-[xe2x80x94NHC(S)NH(CH2)3xe2x80x94N-morpholino]benzyl,
4-[xe2x80x94NHC(O)CH(CH2CH2CH2CH2NH2)NHBoc]benzyl,
4-[xe2x80x94C(O)NH2]benzyl,
4-[xe2x80x94NHC(O)NH-3xe2x80x2-methoxyphenyl]benzyl,
4-[xe2x80x94OCH2CH2-indol-3xe2x80x2-yl]benzyl,
4-[xe2x80x94OCH2C(O)NH-benzyl]benzyl,
4-[xe2x80x94OCH2C(O)O-benzyl]benzyl,
4-[xe2x80x94OCH2C(O)OH]benzyl,
4-[xe2x80x94OCH2-2xe2x80x2xe2x80x94(4xe2x80x2,5xe2x80x2-dihydro)imidazolyl]benzyl,
xe2x80x94CH2C(O)NHCH2xe2x80x94(4-dimethylamino)phenyl,
xe2x80x94CH2C(O)NHCH2xe2x80x94(4-dimethylamino)phenyl,
4xe2x80x94[xe2x80x94NHC(O)-Lxe2x80x942xe2x80x2-pyrrolidinyl-Nxe2x80x94SO2xe2x80x944xe2x80x2-methylphenyl]benzyl,
4xe2x80x94[xe2x80x94NHC(O)NHCH2CH2CH3]benzyl,
4-aminobenzyl]benzyl,
4xe2x80x94[xe2x80x94OCH2CH2xe2x80x941xe2x80x94(4-hydroxyxe2x80x944xe2x80x94(3-methoxypyrrolxe2x80x942-yl)-piperazinyl]benzyl,
4xe2x80x94[xe2x80x94Oxe2x80x94(N-methylpiperidinxe2x80x944xe2x80x2-yl)]benzyl,
3-methoxybenzyl,
4xe2x80x94[xe2x80x94NHC(O)-piperidinxe2x80x943xe2x80x2-yl]benzyl,
4xe2x80x94[xe2x80x94NHC(O)-pyridinxe2x80x942xe2x80x2-yl]benzyl,
4xe2x80x94[xe2x80x94NHCH2xe2x80x94(4xe2x80x2-chlorophenyl)]benzyl,
4xe2x80x94[xe2x80x94NHC(O)xe2x80x94(Nxe2x80x94(4xe2x80x2CH3xe2x80x94xcfx86xe2x80x94SO2)-L-pyrrolidinxe2x80x942xe2x80x2-yl)]benzyl,
4xe2x80x94[xe2x80x94NHC(O)NHCH2CH2xe2x80x94xcfx86]benzyl,
4xe2x80x94[xe2x80x94OCH2C(O)NH2]benzyl,
4xe2x80x94[xe2x80x94OCH2C(O)NH-t-butyl]benzyl,
4xe2x80x94[xe2x80x94OCH2CH2xe2x80x941xe2x80x94(4-hydroxyxe2x80x944-phenyl)-piperidinyl]benzyl,
4xe2x80x94[xe2x80x94NHSO2xe2x80x94CHxe2x95x90CH2]benzyl,
4xe2x80x94[xe2x80x94NHSO2xe2x80x94CH2CH2Cl]benzyl,
xe2x80x94CH2C(O)NHCH2CH2N(CH3)2,
4xe2x80x94[(1xe2x80x2-Cbz-piperidinxe2x80x944xe2x80x2-yl)C(O)NHxe2x80x94]benzyl,
4xe2x80x94[(1xe2x80x2-Boc-piperidinxe2x80x944xe2x80x2-yl)C(O)NHxe2x80x94]benzyl,
4xe2x80x94[(2xe2x80x2-bromophenyl)C(O)NHxe2x80x94]benzyl,
4xe2x80x94[xe2x80x94NHC(O)-pyridinxe2x80x944xe2x80x2-yl]benzyl,
4xe2x80x94[(4xe2x80x2(CH3)2NC(O)Oxe2x80x94)phenyl)xe2x80x94C(O)NHxe2x80x94]benzyl,
4xe2x80x94[xe2x80x94NHC(O)xe2x80x941xe2x80x2-methylpiperidinxe2x80x944xe2x80x2-ylxe2x80x94]benzyl,
4xe2x80x94(dimethylamino)benzyl,
4xe2x80x94[xe2x80x94NHC(O)xe2x80x94(1xe2x80x2-N-Boc)-piperidinxe2x80x942xe2x80x2-yl]benzyl,
3xe2x80x94[xe2x80x94NHC(O)-pyridinxe2x80x944xe2x80x2-yl]benzyl,
4xe2x80x94[(tert-butylxe2x80x94O(O)CCH2xe2x80x94O-benzyl)xe2x80x94NHxe2x80x94]benzyl,
[BocNHCH2C(O)NHxe2x80x94]butyl,
4-benzylbenzyl,
2-hydroxyethyl,
4xe2x80x94[(Et)2NCH2CH2CH2NHC(S)NHxe2x80x94]benzyl,
4xe2x80x94[(1xe2x80x2-Bocxe2x80x944xe2x80x2-hydroxypyrrolidinxe2x80x942xe2x80x2-yl)C(O)NHxe2x80x94]benzyl,
4xe2x80x94[xcfx86CH2CH2CH2NHC(S)NHxe2x80x94]benzyl,
4xe2x80x94[(perhydroindolinxe2x80x942xe2x80x2-yl)C(O)NHxe2x80x94]benzyl,
2xe2x80x94[4-hydroxyxe2x80x944xe2x80x94(3-methoxythienxe2x80x942-yl)piperidinxe2x80x941-yl]ethyl,
4xe2x80x94[(1xe2x80x2-Boc-perhydroindolinxe2x80x942xe2x80x2-yl)xe2x80x94C(O)NHxe2x80x94]benzyl,
4xe2x80x94[Nxe2x80x943-methylbutyl-N-trifluoromethanesulfonyl)amino]benzyl,
4xe2x80x94[N-vinylsulfonyl)amino]benzyl,
4xe2x80x94[2xe2x80x94(2-azabicyclo[3.2.2]octanxe2x80x942-yl)ethylxe2x80x94Oxe2x80x94]benzyl,
4xe2x80x94[4 xe2x80x2-hydroxypyrrolidinxe2x80x942 xe2x80x2-yl)C(O)NHxe2x80x94]benzyl,
4xe2x80x94(xcfx86NHC(S)NH)benzyl,
4xe2x80x94(EtNHC(S)NH)benzyl,
4xe2x80x94(xcfx86CH2NHC(S)NH)benzyl,
3xe2x80x94[(1xe2x80x2-Boc-piperidinxe2x80x942xe2x80x2-yl)C(O)NHxe2x80x94]benzyl,
3xe2x80x94[piperidinxe2x80x942xe2x80x2-ylxe2x80x94C(O)NHxe2x80x94]benzyl,
4xe2x80x94[(3xe2x80x2-Boc-thiazolidinxe2x80x944xe2x80x2-yl)C(O)NHxe2x80x94]benzyl,
4xe2x80x94(pyridinxe2x80x943xe2x80x2-yl-NHC(S)NH)benzyl,
4xe2x80x94(CH3xe2x80x94NHC(S)NH)benzyl,
4xe2x80x94(H2NCH2CH2CH2C(O)NH)benzyl,
4xe2x80x94(BocHNCH2CH2CH2C(O)NH)benzyl,
4xe2x80x94(pyridinxe2x80x944xe2x80x2-yl-CH2NH)benzyl,
4xe2x80x94[(N,N-di(4-N,N-dimethylamino)benzyl)amino]benzyl,
4xe2x80x94[(1 -Cbz-piperidinxe2x80x944-yl)C(O)NHxe2x80x94]butyl,
4xe2x80x94[xcfx86CH2OCH2(BocHN)CHC(O)NH]benzyl,
4xe2x80x94[(piperidinxe2x80x944xe2x80x2-yl)C(O)NHxe2x80x94]benzyl,
4xe2x80x94[(pyrrolidinxe2x80x942xe2x80x2-yl)C(O)NHxe2x80x94]benzyl,
4xe2x80x94(pyridinxe2x80x943xe2x80x2-yl-C(O)NH)butyl,
4xe2x80x94(pyridinxe2x80x944xe2x80x2-yl-C(O)NH)butyl,
4xe2x80x94(pyridinxe2x80x943xe2x80x2-yl-C(O)NH)benzyl,
4xe2x80x94[CH3NHCH2CH2CH2C(O)NHxe2x80x94]benzyl,
4xe2x80x94[CH3N(Boc)CH2CH2CH2C(O)NHxe2x80x94]benzyl,
4xe2x80x94(aminomethyl)benzyl,
4xe2x80x94[xcfx86CH2OCH2(H2N)CHC(O)NH]benzyl,
4xe2x80x94[(1xe2x80x2,4xe2x80x2-di(Boc)piperazinxe2x80x942xe2x80x2-yl)-C(O)NHxe2x80x94]benzyl,
4xe2x80x94[(piperazinxe2x80x942xe2x80x2-yl)xe2x80x94C(O)NHxe2x80x94]benzyl,
4xe2x80x94[(N-toluenesulfonylpyrrolidinxe2x80x942xe2x80x2-yl)C(O)NHxe2x80x94]butyl,
4xe2x80x94[xe2x80x94NHC(O)xe2x80x944xe2x80x2-piperidinyl]butyl,
4xe2x80x94[xe2x80x94NHC(O)xe2x80x941xe2x80x2-N-Boc-piperidinxe2x80x942xe2x80x2-yl]benzyl,
4xe2x80x94[xe2x80x94NHC(O)-piperidinxe2x80x942xe2x80x2-yl]benzyl,
4xe2x80x94[(1xe2x80x2-N-Bocxe2x80x942xe2x80x2,3xe2x80x2-dihydroindolinxe2x80x942xe2x80x2-yl)xe2x80x94C(O)NH]benzyl,
4xe2x80x94(pyridinxe2x80x943xe2x80x2-yl-CH2NH)benzyl,
4xe2x80x94[(piperidinxe2x80x941xe2x80x2-yl)C(O)CH2xe2x80x94Oxe2x80x94]benzyl,
4xe2x80x94[(CH3)2CH)2NC(O)CH2xe2x80x94Oxe2x80x94]benzyl,
4xe2x80x94[HO(O)C(Cbz-NH)CHCH2CH2xe2x80x94C(O)NHxe2x80x94]benzyl,
4xe2x80x94[xcfx86CH2O(O)C(Cbz-NH)CHCH2CH2xe2x80x94C(O)NHxe2x80x94]benzyl,
4xe2x80x94[xe2x80x94NHC(O)xe2x80x942xe2x80x2-methoxyphenyl]benzyl,
4xe2x80x94[(pyrazinxe2x80x942xe2x80x2-yl)C(O)NHxe2x80x94]benzyl,
4xe2x80x94[HO(O)C(NH2)CHCH2CH2xe2x80x94C(O)NHxe2x80x94]benzyl,
4xe2x80x94(2xe2x80x2-formylxe2x80x941xe2x80x2,2xe2x80x2,3xe2x80x2, 4xe2x80x2-tetrahydroisoquinolinxe2x80x943xe2x80x2-yl-CH2NHxe2x80x94)benzyl,
N-Cbz-NHCH2xe2x80x94,
4xe2x80x94[(4xe2x80x2-methylpiperazinxe2x80x941xe2x80x2-yl)C(O)Oxe2x80x94]benzyl,
4xe2x80x94[CH3(N-Boc)NCH2C(O)NHxe2x80x94]benzyl,
4xe2x80x94[xe2x80x94NHC(O)xe2x80x94(1xe2x80x2,2xe2x80x2,3xe2x80x2, 4xe2x80x2-tetrahydro-N-Boc-isoquinolinxe2x80x943xe2x80x2-yl]-benzyl,
4xe2x80x94[CH3NHCH2C(O)NHxe2x80x94]benzyl,
(CH3)2NC(O)CH2xe2x80x94,
4xe2x80x94(N-methylacetamido)benzyl,
4xe2x80x94(1xe2x80x2,2xe2x80x2,3xe2x80x2,4xe2x80x2-tetrahydroisoquinolinxe2x80x943xe2x80x2-yl-CH2NHxe2x80x94)benzyl,
4xe2x80x94[(CH3)2NHCH2C(O)NHxe2x80x94]benzyl,
(1-toluenesulfonylimidizolxe2x80x944-yl)methyl,
4xe2x80x94[(1xe2x80x2-Boc-piperidinxe2x80x944xe2x80x2-yl)C(O)NHxe2x80x94]benzyl,
4-trifluoromethylbenzyl,
4xe2x80x94[(2xe2x80x2-bromophenyl)C(O)NHxe2x80x94]benzyl,
4xe2x80x94[(CH3)2NC(O)NHxe2x80x94]benzyl,
4xe2x80x94[CH3OC(O)NHxe2x80x94]benzyl,
4xe2x80x94[(CH3)2NC(O)Oxe2x80x94]benzyl,
4xe2x80x94[(CH3)2NC(O)N(CH3)xe2x80x94]benzyl,
4xe2x80x94[CH3OC(O)N(CH3)xe2x80x94]benzyl,
4xe2x80x94(N-methyltrifluoroacetamido)benzyl,
4xe2x80x94[(1xe2x80x2-methoxycarbonylpiperidinxe2x80x944xe2x80x2-yl)C(O)NHxe2x80x94]benzyl,
4xe2x80x94[(4xe2x80x2-phenylpiperidinxe2x80x944xe2x80x2-yl)C(O)NHxe2x80x94]benzyl,
4xe2x80x94[(4xe2x80x2-phenylxe2x80x941xe2x80x2-Boc-piperidinxe2x80x944xe2x80x2-yl)-C(O)NHxe2x80x94]benzyl,
4xe2x80x94[(piperidinxe2x80x944xe2x80x2-yl)C(O)Oxe2x80x94]benzyl, 4xe2x80x94[(1xe2x80x2-methylpiperidinxe2x80x944xe2x80x2-yl)xe2x80x94Oxe2x80x94]benzyl,
4xe2x80x94[(1xe2x80x2-methylpiperidinxe2x80x944xe2x80x2-yl)C(O)Oxe2x80x94]benzyl,
4xe2x80x94[(4xe2x80x2-methylpiperazinxe2x80x941xe2x80x2-yl)C(O)NHxe2x80x94]benzyl,
3xe2x80x94[(CH3)2NC(O)Oxe2x80x94]benzyl,
4xe2x80x94[(4xe2x80x2-phenylxe2x80x941xe2x80x2-Boc-piperidinxe2x80x944xe2x80x2-yl)xe2x80x94C(O)Oxe2x80x94]benzyl,
4xe2x80x94(N-toluenesulfonylamino)benzyl,
4xe2x80x94[(CH3)3CC(O)NHxe2x80x94]benzyl,
4xe2x80x94[(morpholinxe2x80x944xe2x80x2-yl)C(O)NHxe2x80x94]benzyl,
4xe2x80x94[(CH3CH2)2NC(O)NHxe2x80x94]benzyl,
4xe2x80x94[xe2x80x94C(O)NHxe2x80x94(4xe2x80x2-piperidinyl)]benzyl,
4xe2x80x94[(2xe2x80x2-trifluoromethylphenyl)C(O)NHxe2x80x94]benzyl,
4xe2x80x94[(2xe2x80x2-methylphenyl)C(O)NHxe2x80x94]benzyl,
4xe2x80x94[(CH3)2NS(O)2Oxe2x80x94]benzyl,
4xe2x80x94[(pyrrolidinxe2x80x942xe2x80x2-yl)C(O)NHxe2x80x94]benzyl,
4xe2x80x94[xe2x80x94NHC(O)-piperidinxe2x80x941xe2x80x2-yl]benzyl,
4xe2x80x94[(thiomorpholinxe2x80x944xe2x80x2-yl)C(O)NHxe2x80x94]benzyl,
4xe2x80x94[(thiomorpholinxe2x80x944xe2x80x2-yl sulfone)xe2x80x94C(O)NHxe2x80x94]benzyl,
4xe2x80x94[(morpholinxe2x80x944xe2x80x2-yl)C(O)Oxe2x80x94]benzyl,
3-nitroxe2x80x944xe2x80x94(CH3OC(O)CH2Oxe2x80x94)benzyl,
(2-benzoxazolinonxe2x80x946-yl)methyl-,
(2Hxe2x80x941,4-benzoxazinxe2x80x943(4H)-onexe2x80x947-yl)methyl-,
4xe2x80x94[(CH3)2NS(O)2NHxe2x80x94]benzyl,
4xe2x80x94[(CH3)2NS(O)2N(CH3)xe2x80x94]benzyl,
4xe2x80x94[(thiomorpholinxe2x80x944xe2x80x2-yl)C(O)Oxe2x80x94]benzyl,
4xe2x80x94[(thiomorpholinxe2x80x944xe2x80x2-yl sulfone)xe2x80x94C(O)Oxe2x80x94]benzyl,
4xe2x80x94[(piperidinxe2x80x941xe2x80x2-yl)C(O)Oxe2x80x94]benzyl,
4xe2x80x94[(pyrrolidinxe2x80x941xe2x80x2-yl)C(O)Oxe2x80x94]benzyl,
4xe2x80x94[(4xe2x80x2-methylpiperazinxe2x80x941xe2x80x2-yl)C(O)Oxe2x80x94]benzyl,
4xe2x80x94[(2xe2x80x2-methylpyrrolidinxe2x80x941xe2x80x2-yl)-,
(pyridinxe2x80x944-yl)methyl-,
4xe2x80x94(piperazinxe2x80x944xe2x80x2-yl)xe2x80x94C(O)Oxe2x80x94]benzyl,
4xe2x80x94[(1xe2x80x2-Boc-piperazinxe2x80x944xe2x80x2-yl)xe2x80x94C(O)Oxe2x80x94]benzyl,
4xe2x80x94[(4xe2x80x2-acetylpiperazinxe2x80x941xe2x80x2-yl)C(O)Oxe2x80x94]benzyl,
pxe2x80x94[(4xe2x80x2-methanesulfonylpiperazinxe2x80x941xe2x80x2-yl)-benzyl,
3-nitroxe2x80x944xe2x80x94[(morpholinxe2x80x944xe2x80x2-yl)xe2x80x94C(O)Oxe2x80x94]benzyl,
4xe2x80x94{[(CH3)2NC(S)]2Nxe2x80x94}benzyl,
N-Bocxe2x80x942-aminoethyl-,
4xe2x80x94[(1,1-dioxothiomorpholinxe2x80x944-yl)xe2x80x94C(O)Oxe2x80x94]benzyl,
4xe2x80x94[(CH3)2NS(O)2xe2x80x94]benzyl,
4xe2x80x94(imidazolidxe2x80x942xe2x80x2-onexe2x80x941xe2x80x2-yl)benzyl,
4xe2x80x94[(piperidinxe2x80x941xe2x80x2-yl)C(O)Oxe2x80x94]benzyl,
1-N-benzyl-imidazolxe2x80x944-yl-CH2xe2x80x94,
3,4-dioxyethylenebenzyl (i.e., 3,4-ethylenedioxybenzyl),
3,4-dioxymethylenebenzyl (i.e., 3,4-methylenedioxybenzyl),
4xe2x80x94[-N(SO2)(CH3)CH2CH2CH2N(CH3)2]benzyl,
4xe2x80x94(3xe2x80x2-formylimidazolidxe2x80x942xe2x80x2-onexe2x80x941xe2x80x2-yl)benzyl,
4xe2x80x94[NHC(O)CH(CH2CH2CH2CH2NH2)NHBoc]benzyl,
[2xe2x80x2xe2x80x94[4xe2x80x3-hydroxyxe2x80x944xe2x80x3xe2x80x94(3xe2x80x2xe2x80x3-methoxythienxe2x80x942xe2x80x2xe2x80x3-yl)piperidinxe2x80x942xe2x80x3-yl]ethoxy]benzyl, and
pxe2x80x94[(CH3)2NCH2CH2N(CH3)C(O)Oxe2x80x94]benzyl.
Preferably, R5 in the above compounds is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl. Even more preferably R5 is selected from the group consisting of 4-methylphenyl, methyl, benzyl, n-butyl, n-hexyl, 4-chlorophenyl, 1-naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2,4,6-trimethylphenyl, 2xe2x80x94(methoxycarbonyl)phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl, 4-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 4xe2x80x94(CH3C(O)NHxe2x80x94)phenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl, 3,5-dixe2x80x94(trifluoromethyl)phenyl, 4-t-butylphenyl, 4-t-butoxyphenyl, 4-nitrophenyl, 2-thienyl, 1-N-methylxe2x80x943-methylxe2x80x945-chloropyrazolxe2x80x944-yl, phenethyl, 1-N-methylimidazolxe2x80x944-yl, 4-bromophenyl, 4-amidinophenyl, 4-methylamidinophenyl, 4xe2x80x94[CH3SC(xe2x95x90NH)]phenyl, 5-chloroxe2x80x942-thienyl, 2,5-dichloro4-thienyl, 1-N-methylxe2x80x944-pyrazolyl, 2-thiazolyl, 5-methylxe2x80x941,3,4-thiadiazolxe2x80x942-yl, 4xe2x80x94[H2NC(S)]phenyl, 4-aminophenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridinxe2x80x943-yl, pyrimidinxe2x80x942-yl, 4xe2x80x94(3xe2x80x2-dimethylamino-n-propoxy)-phenyl, and 1-methylpyrazolxe2x80x944-yl.
Preferably, R13 in the above compounds is selected from hydrogen or C1-6 alkyl; more preferably, hydrogen or C1-3 alkyl; and still more preferably, hydrogen or methyl.
In a preferred embodiment, R14 in the above compounds is preferably hydrogen and R15 is preferably C1-10 alkyl or Cy-C1-10 alkyl, wherein alkyl is optionally substituted with one to four substituents selected from phenyl and Rx, and Cy is optionally substituted with one to four substituents independently selected from Ry, or R14 and R15 and the carbon to which they are attached together from a 3-7 membered mono- or bicyclic carbon only ring. For the purpose of R15, Cy is preferably aryl, more preferably phenyl. In a preferred embodiment, R15 is phenyl-C1-3 alkyl, wherein phenyl is optionally substituted with one or two groups selected from Ry. Additional preferred embodiments for R14 and R15 are disclosed in International Patent Application Publication No. WO 98/53814, which application is incorporated herein by reference in its entirety.
In a preferred embodiment of the above compounds, R16 is substituted amino; R17 and/or R20 are hydrogen; and R18 and/or R21 are alkyl, substituted alkyl, aryl or substituted aryl.
In a preferred embodiment, R23 in the above compounds is hydrogen. Preferably, R24 in the above compounds is Ar1xe2x80x94Ar2xe2x80x94C1-10 alkyl wherein Ar1 and Ar2 are optionally substituted with from 1 to 4 groups independently selected from Rb and R25 is hydrogen. More preferably, R24 is Ar1xe2x80x94Ar2xe2x80x94C1-3 alkyl wherein Ar1 and Ar2 are optionally substituted with from 1 to 4 groups independently selected from Rb; still more preferably, R24 is xe2x80x94CH2xe2x80x94Ar1xe2x80x94Ar1 and R25 is hydrogen. Additional preferred embodiments are disclosed in International Patent Application Publication No. WO 98/53817, which application is incorporated herein by reference in its entirety.
Preferably, R3 and R3xe2x80x2, or R4 and R5, or R24 and R25 are derived from L-amino acids or other similarly configured starting materials.
Alternatively, racemic mixtures can be used.
Preferably, x in the above compounds is an integer from 1 to 4.
This invention also provides methods for binding VLAxe2x80x944 in a biological sample which method comprises contacting the biological sample with a compound of this invention under conditions wherein said compound binds to VLAxe2x80x944.
The pharmaceutical compositions may be used to treat disease conditions mediated by VLAxe2x80x944 or leucocyte adhesion. Such disease conditions include, by way of example, asthma, Alzheimer""s disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn""s disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
Other disease conditions include, but are not limited to, inflammatory conditions such as erythema nodosum, allergic conjunctivitis, optic neuritis, uveitis, allergic rhinitis, ankylosing spondylitis, psoriatic arthritis, vasculitis, Reiter""s syndrome, systemic lupus erythematosus, progressive systemic sclerosis, polymyositis, dermatomyositis, Wegner""s granulomatosis, aortitis, sarcoidosis, lymphocytopenia, temporal arteritis, pericarditis, myocarditis, congestive heart failure, polyarteritis nodosa, hypersensitivity syndromes, allergy, hypereosinophilic syndromes, Churg-Strauss syndrome, chronic obstructive pulmonary disease, hypersensitivity pneumonitis, chronic active hepatitis, interstitial cystitis, autoimmune endocrine failure, primary biliary cirrhosis, autoimmune aplastic anemia, chronic persistent hepatitis and thyroiditis.
Preferred compounds of this invention include those set forth in the Tables below:
Accordingly, this invention is also directed to each of the following compounds:
Nxe2x80x94(2-chloroxe2x80x945-nitropyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,Nxe2x80x945 dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94[5xe2x80x94(Nxe2x80x944-toluenesulfonylamino)pyrimidinxe2x80x944-yl]-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester,
Nxe2x80x94[5xe2x80x94(Nxe2x80x944-toluenesulfonylamino)pyrimidinxe2x80x944-yl]-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94[5xe2x80x94(N-methyl-Nxe2x80x944-toluenesulfonylamino)pyrimidinxe2x80x944-yl]-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester,
Nxe2x80x94[5xe2x80x94(N-methyl-Nxe2x80x944-toluenesulfonylamino)pyrimidinxe2x80x944-yl]-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94[5xe2x80x94(N,N-dixe2x80x944-toluenesulfonylamino)pyrimidinxe2x80x944-yl]-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94[5xe2x80x94[Nxe2x80x94(1-Nxe2x80x2-methylpyrazolxe2x80x944-yl]sulfonyl)-N-methylaminopyrimidinxe2x80x944-yl]-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94[5xe2x80x94(N-methyl-Nxe2x80x944-toluenesulfonylamino)pyrimidinxe2x80x944-yl]-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine isopropyl ester,
Nxe2x80x94[5xe2x80x94(N-methyl-Nxe2x80x943-pyridylsulfonylamino)pyrimidinxe2x80x944-yl]-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester,
Nxe2x80x94(5xe2x80x94(N-methyl-Nxe2x80x94(1-butylpyrazolxe2x80x944-yl)sulfonylamino)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(2,4-dimethoxypyrimidinxe2x80x945-yl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(2,6-difluorophenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(2-hydroxymethylphenyl)pyrimidinxe2x80x944-y1)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-cyclohexylamino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-Nxe2x80x94(1-methylpiperidinxe2x80x944-yl)amino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-ethyl-N-isopropylamino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(2,4xe2x80x946-trimethylphenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5-isopropylpyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-butylamino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-ethyl-N-propylamino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N,N-diethylamino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-ethylamino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5-benzyloxypyrimidinxe2x80x944-yl)-L-phenylalanine.
Nxe2x80x94(5-benzyloxypyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(N-methyl-Nxe2x80x944-toluenesulfonylamino)pyrimidinxe2x80x944-yl)-L-phenylalanine,
Nxe2x80x94(5xe2x80x94(N-methyl-Nxe2x80x943-pyridinesulfonylamino)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5-phenylpyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(3xe2x80x94(N-methyl-Nxe2x80x944-toluenesulfonylamino)pyrazinxe2x80x942-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(2,2,2-trifluoroethyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(N-methyl-Nxe2x80x943-pyridinesulfonylamino)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(4-methylpiperazinxe2x80x941-ylcarbonyloxy)phenylalanine isopropyl ester,
Nxe2x80x94(5-benzylpyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine.
Nxe2x80x94(5xe2x80x94(Amethyl-Nxe2x80x943-pyridinesulfonylamino)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(4-methylpiperazin- -ylcarbonyloxy)phenylalanine tert-butyl ester,
Nxe2x80x94(5xe2x80x94(2-trifluoromethylphenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(2-N, N-dimethylcarbamylethyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(N-methyl-Nxe2x80x943xe2x80x94(1-methylpyrazole)sulfonylamino)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine isopropyl ester,
Nxe2x80x94(6-phenylpyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(6xe2x80x94(2-trifluoromethylphenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(6xe2x80x94(2-hydroxymethylphenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5-cyclohexylpyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-Nxe2x80x942-furanmethylamino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-Nxe2x80x944-chlorophenylamino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(3-thienyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(2-thienyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-Nxe2x80x942-hydroxyethylamino)xe2x80x945xe2x80x94(2-fluorophenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(piperidinxe2x80x941-yl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(1-propylbutyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-cyclobutylamino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N,N-bisxe2x80x94(2-hydroxyethyl)amino)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N,N-bisxe2x80x94(2-hydroxyethyl)amino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-phenylamino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(isopropoxy)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-Nxe2x80x943-methylbutylamino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine.
Nxe2x80x94(2xe2x80x94(N-methylamino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
-Nxe2x80x94(2xe2x80x94(2-tolyl)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-Nxe2x80x942-hydroxyethylamino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-Nxe2x80x942-methylpropylamino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-propylamino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N,N-dimethylamino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-cyclohexylamino)xe2x80x945xe2x80x94(3-pyridyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(2-phenylxe2x80x942,2-difluoroethyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(2-phenylxe2x80x942,2-difluoroethyl)xe2x80x946-chloropyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(2-phenylethyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-cyclohexylamino)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5-propylpyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(2-methoxyphenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(2-fluorophenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-Methyl-N-isopropylamino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-isopropylamino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(2-phenylethyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine isopropyl ester,
Nxe2x80x94(3xe2x80x94(N-methyl-Nxe2x80x944-toluenesulfonylamino)pyrazinxe2x80x942-yl)-L-phenylalanine isopropyl ester,
Nxe2x80x94(5xe2x80x94(2-phenylethyl)pyrimidinxe2x80x944-yl)-L-phenylalanine isopropyl ester,
Nxe2x80x94(5xe2x80x94(N-methyl-Nxe2x80x943-pyridinesulfonylamino)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(4-methylpiperazinxe2x80x941-ylcarbonyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-cyclohexylamino)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-L4xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-cyclohexylamino)xe2x80x945-ethylpyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine isopropyl ester,
Nxe2x80x94(5xe2x80x94(3-nitrophenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(3-pyridyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(2-phenylethyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2-N,N-dimethylaminoxe2x80x945xe2x80x94(N-methyl-Nxe2x80x944-toluenesulfonylamino)pyrimidinxe2x80x944-yl)-L-phenylalanine,
Nxe2x80x94(5xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-cyclohexylamino)xe2x80x945xe2x80x94(2-methoxyphenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-isopropylamino)xe2x80x945xe2x80x94(2-fluorophenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-isopropylamino)xe2x80x945xe2x80x94(2-fluorophenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2-methoxyphenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-cyclohexylamino)xe2x80x945xe2x80x94(2,6-difluorophenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2,6-difluorophenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-cyclohexylamino)xe2x80x945xe2x80x94(2-hydroxymethylphenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N,N-bisxe2x80x94(2-hydroxyethyl)amino)xe2x80x945xe2x80x94(2,4,6-trimethylphenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-cyclohexylamino)xe2x80x945xe2x80x94(2-trifluoromethylphenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2-cyanophenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-cyclohexylamino)xe2x80x945xe2x80x94(3-thienyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-cyclohexylamino)xe2x80x945xe2x80x94(2-thienyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(4-trifluoromethylphenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-cyclohexylamino)xe2x80x945xe2x80x94(3-pyridyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-cyclohexylamino)xe2x80x945xe2x80x94(3-nitrophenyl)pyrimidinxe2x80x944-y1)-Lxe2x80x944xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-cyclohexylamino)xe2x80x945xe2x80x94(2,6-dichlorophenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-cyclohexylamino)xe2x80x945xe2x80x94(4-pyridyl)pyrimidinxe2x80x944-y1)-Lxe2x80x944xe2x80x94(3-hydroxymethylphenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-ethyl-N-isopropylamino)xe2x80x945xe2x80x94(2,6-dimethoxyphenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-cyclohexylamino)xe2x80x945xe2x80x94(2,3-dichlorophenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-ethylamino)xe2x80x945xe2x80x94(2,4,6-trimethylphenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2-cyanophenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-isopropylamino)xe2x80x945xe2x80x94(2,4,6-trimethylphenyl)pyrimidin4-yl)-Lxe2x80x944xe2x80x94(3-pyridyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N,N-bisxe2x80x94(2-hydroxyethyl)amino)xe2x80x945xe2x80x94(2,4,6-trimethylphenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2-cyanophenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-Nxe2x80x94(1-methylpiperidinxe2x80x944-yl)amino)xe2x80x945xe2x80x94(2-cyanophenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2,6-difluorophenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-ethyl-N-isopropylamino)xe2x80x945xe2x80x94(2,4,6-trimethylphenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(o-tolyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-Nxe2x80x944-chlorophenylamino)xe2x80x945xe2x80x94(2,4,6-trimethylphenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(5xe2x80x94(N-methyl-Nxe2x80x942xe2x80x94(phenyl)ethylamino)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(N-methyl-N-hexylamino)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(N-methyl-N-isopropylamino)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(N-methyl-N-tert-butylamino)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(N-ethyl-N-isopropylamino)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(N-methyl-Nxe2x80x942xe2x80x94(4-pyridyl)ethyl-pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(N-methyl-Nxe2x80x942xe2x80x94(phenyl)ethylamino)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(4xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(5xe2x80x94(N-methyl-N-hexylamino)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(5xe2x80x94(N-methyl-N-isopropylamino)pyrimidinxe2x80x944-yl)-L4xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(5xe2x80x94(N-methyl-N-tert-butylamino)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(5xe2x80x94(N-ethyl-N-isopropylamino)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(5xe2x80x94(N-methyl-Nxe2x80x942xe2x80x94(4-pyridyl)ethyl-pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-cyclohexylamino)xe2x80x945-ethylpyrimidinxe2x80x944-yl)-L4-N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(4xe2x80x94(N,N-di-n-hexylamino)xe2x80x941,1-dioxoxe2x80x941,2,5-thiadiazolxe2x80x943-yl)-L-tyrosine,
Nxe2x80x94(4xe2x80x94(N,N-di-n-hexylamino)xe2x80x941,1-dioxoxe2x80x941,2,5-thiadiazolxe2x80x943-yl)-Lxe2x80x944xe2x80x94(N,N-dimethylcarbamyloxy)phenylalanine,
Nxe2x80x94(4xe2x80x94(N,N-dimethylamino)xe2x80x941-oxoxe2x80x941,2,5-thiadiazolxe2x80x943-yl)-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester,
Nxe2x80x94[4xe2x80x94(2xe2x80x94(3-methylphenylaminocarbonylamino)ethxe2x80x941-ylamino)xe2x80x941,1-dioxoxe2x80x941,2,5-thiadiazolxe2x80x943-yl]-Lxe2x80x944-N,N-dimethylcarbamyloxy)phenylalanine
Nxe2x80x94(4xe2x80x94(N,N-di-n-hexylamino)xe2x80x941,1-dioxoxe2x80x941,2,5-thiadiazolxe2x80x943-yl)-Lxe2x80x944xe2x80x94(4-methylpiperazinxe2x80x941-ylcarbonyloxy)phenylalanine,
Nxe2x80x94(5xe2x80x94(2,2,2-trifluoroethyl)pyrimidinxe2x80x944-yl)-L4xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-cyclohexyl-N-methyl)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(5xe2x80x94(2-fluorophenyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(2xe2x80x94(N-methyl-N-propyl)xe2x80x945xe2x80x94(2-tolyl)pyrimidinxe2x80x944-yl)-Lxe2x80x944xe2x80x94(2,6-dimethoxyphenyl)phenylalanine,
Nxe2x80x94(3-chloropyrazinxe2x80x942-yl)-Lxe2x80x944xe2x80x94[1xe2x80x94(tert-butoxycarbonyl)piperidinxe2x80x944-ylcarbonylamino]phenylalanine ethyl ester,
and pharmaceutically acceptable salts thereof.
As above, this invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLAxe2x80x944. However, prior to describing this invention in further detail, the following terms will first be defined.
As used herein, xe2x80x9calkylxe2x80x9d refers to alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl and the like.
xe2x80x9cSubstituted alkylxe2x80x9d refers to an alkyl group, preferably of from 1 to 10 carbon atoms, having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and dixe2x80x94(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cAlkoxyxe2x80x9d refers to the group xe2x80x9calkylxe2x80x94Oxe2x80x94xe2x80x9d which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
xe2x80x9cSubstituted alkoxyxe2x80x9d refers to the group xe2x80x9csubstituted alkylxe2x80x94Oxe2x80x94xe2x80x9d.
xe2x80x9cAlkenoxyxe2x80x9d refers to the group xe2x80x9calkenylxe2x80x94Oxe2x80x94xe2x80x9d.
xe2x80x9cSubstituted alkenoxyxe2x80x9d refers to the group xe2x80x9csubstituted alkenylxe2x80x94Oxe2x80x94xe2x80x9d.
xe2x80x9cAcylxe2x80x9d refers to the groups Hxe2x80x94C(O)xe2x80x94, alkyl-C(O)xe2x80x94, substituted alkyl-C(O)xe2x80x94, alkenyl-C(O)xe2x80x94, substituted alkenyl-C(O)xe2x80x94, alkynyl-C(O)xe2x80x94, substituted alkynyl-C(O)xe2x80x94 cycloalkyl-C(O)xe2x80x94, substituted cycloalkyl-C(O)xe2x80x94, aryl-C(O)xe2x80x94, substituted aryl-C(O)xe2x80x94, heteroaryl-C(O)xe2x80x94, substituted heteroaryl-C(O), heterocyclic-C(O)xe2x80x94, and substituted heterocyclic-C(O)xe2x80x94 wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAcylaminoxe2x80x9d refers to the group xe2x80x94C(O)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cThiocarbonylaminoxe2x80x9d refers to the group xe2x80x94C(S)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where each R is joined to form, together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAcyloxyxe2x80x9d refers to the groups alkyl-C(O)Oxe2x80x94, substituted alkyl-C(O)Oxe2x80x94, alkenyl-C(O)Oxe2x80x94, substituted alkenyl-C(O)Oxe2x80x94, alkynyl-C(O)Oxe2x80x94, substituted alkynyl-C(O)Oxe2x80x94, aryl-C(O)Oxe2x80x94, substituted aryl-C(O)Oxe2x80x94, cycloalkyl-C(O)Oxe2x80x94, substituted cycloalkyl-C(O)Oxe2x80x94, heteroaryl-C(O)Oxe2x80x94, substituted heteroaryl-C(O)Oxe2x80x94, heterocyclic-C(O)Oxe2x80x94, and substituted heterocyclic-C(O)Oxe2x80x94 wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cOxysulfonylxe2x80x9d refers to the groups alkyl-SO2Oxe2x80x94, substituted alkyl-SO2Oxe2x80x94, alkenyl-SO2Oxe2x80x94, substituted alkenyl-SO2Oxe2x80x94, alkynyl-SO2Oxe2x80x94, substituted alkynyl-SO2Oxe2x80x94, aryl-SO2Oxe2x80x94, substituted aryl-SO2Oxe2x80x94, cycloalkyl-SO2Oxe2x80x94, substituted cycloalkyl-SO2Oxe2x80x94, heteroaryl-SO2Oxe2x80x94, substituted heteroaryl-SO2Oxe2x80x94, heterocyclic-SO2Oxe2x80x94, and substituted heterocyclic-SO2Oxe2x80x94 wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAlkenylxe2x80x9d refers to alkenyl group preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation.
xe2x80x9cSubstituted alkenylxe2x80x9d refers to alkenyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and dixe2x80x94(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkenyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkenyl/substituted alkenyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cAlkynylxe2x80x9d refers to alkynyl group preferably having from 2 to 10 carbon atoms and more preferably 3 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation.
xe2x80x9cSubstituted alkynylxe2x80x9d refers to alkynyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono-and dixe2x80x94(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkynyl/substituted alkynyl groups substituted with xe2x80x94SO-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cAmidinoxe2x80x9d refers to the group H2NC(xe2x95x90NH)xe2x80x94 and the term xe2x80x9calkylamidinoxe2x80x9d refers to compounds having 1 to 3 alkyl groups (e.g., alkylHNC(xe2x95x90NH)xe2x80x94).
xe2x80x9cThioamidinoxe2x80x9d refers to the group RSC(xe2x95x90NH)xe2x80x94 where R is hydrogen or alkyl.
xe2x80x9cAminoxe2x80x9d refers to the group xe2x80x94NH2.
xe2x80x9cSubstituted aminoxe2x80x9d refers to the group xe2x80x94NRR, where each R group is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic, provided that both R groups are not hydrogen; or the R groups can be joined together with the nitrogen atom to form a heterocyclic or substituted heterocyclic ring.
xe2x80x9cAminoacylxe2x80x9d refers to the groups xe2x80x94NRC(O)alkyl, xe2x80x94NRC(O)substituted alkyl, xe2x80x94NRC(O)cycloalkyl, xe2x80x94NRC(O)substituted cycloalkyl, xe2x80x94NRC(O)alkenyl, xe2x80x94NRC(O)substituted alkenyl, xe2x80x94NRC(O)alkynyl, xe2x80x94NRC(O)substituted alkynyl, xe2x80x94NRC(O)aryl, xe2x80x94NRC(O)substituted aryl, xe2x80x94NRC(O)heteroaryl, xe2x80x94NRC(O)substituted heteroaryl, xe2x80x94NRC(O)heterocyclic, and xe2x80x94NRC(O)substituted heterocyclic where R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAminosulfonylxe2x80x9d refers to the groups xe2x80x94NRSO2alkyl, xe2x80x94NRSO2substituted alkyl, xe2x80x94NRSO2cycloalkyl, xe2x80x94NRSO2substituted cycloalkyl, xe2x80x94NRSO2alkenyl, xe2x80x94NRSO2substituted alkenyl, xe2x80x94NRSO2alkynyl, xe2x80x94NRSO2substituted alkynyl, xe2x80x94NRSO2aryl, xe2x80x94NRSO2substituted aryl, xe2x80x94NRSO2heteroaryl, xe2x80x94NRSO2substituted heteroaryl, xe2x80x94NRSO2heterocyclic, and xe2x80x94NRSO2substituted heterocyclic where R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAminocarbonyloxyxe2x80x9d refers to the groups xe2x80x94NRC(O)O-alkyl, xe2x80x94NRC(O)O-substituted alkyl, xe2x80x94NRC(O)O-alkenyl, xe2x80x94NRC(O)O-substituted alkenyl, xe2x80x94NRC(O)O-alkynyl, xe2x80x94NRC(O)O-substituted alkynyl, xe2x80x94NRC(O)O-cycloalkyl, xe2x80x94NRC(O)O-substituted cycloalkyl, xe2x80x94NRC(O)O-aryl, xe2x80x94NRC(O)O-substituted aryl, xe2x80x94NRC(O)O-heteroaryl, xe2x80x94NRC(O)O-substituted heteroaryl, xe2x80x94NRC(O)O-heterocyclic, and xe2x80x94NRC(O)O-substituted heterocyclic where R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAminosulfonyloxyxe2x80x9d refers to the groups xe2x80x94NRSO2O-alkyl, xe2x80x94NRSO2O-substituted alkyl, xe2x80x94NRSO2O-alkenyl, xe2x80x94NRSO2O-substituted alkenyl, xe2x80x94NRSO2O-alkynyl, xe2x80x94NRSO2O-substituted alkynyl, xe2x80x94NRSO2O-cycloalkyl, xe2x80x94NRSO2O-substituted cycloalkyl, xe2x80x94NRSO2O-aryl, xe2x80x94NRSO2O-substituted aryl, xe2x80x94NRSO2O-heteroaryl, xe2x80x94NRSO2O-substituted heteroaryl, xe2x80x94NRSO2O-heterocyclic, and xe2x80x94NRSO2O-substituted heterocyclic where R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cOxycarbonylaminoxe2x80x9d refers to the groups xe2x80x94OC(O)NH2, xe2x80x94OC(O)NRR, xe2x80x94OC(O)NR-alkyl, xe2x80x94OC(O)NR-substituted alkyl, xe2x80x94OC(O)NR-alkenyl, xe2x80x94OC(O)NR-substituted alkenyl, xe2x80x94OC(O)NR-alkynyl, xe2x80x94OC(O)NR-substituted alkynyl, xe2x80x94OC(O)NR-cycloalkyl, xe2x80x94OC(O)NR-substituted cycloalkyl, xe2x80x94OC(O)NR-aryl, xe2x80x94OC(O)NR-substituted aryl, xe2x80x94OC(O)NR-heteroaryl, xe2x80x94OC(O)NR-substituted heteroaryl, xe2x80x94OC(O)NR-heterocyclic, and xe2x80x94OC(O)NR-substituted heterocyclic where R is hydrogen, alkyl or where each R is joined to form, together with the nitrogen atom a heterocyclic or substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cOxythiocarbonylaminoxe2x80x9d refers to the groups xe2x80x94OC(S)NH2, xe2x80x94OC(S)NRR, xe2x80x94OC(S)NR-alkyl, xe2x80x94OC(S)NR-substituted alkyl, xe2x80x94OC(S)NR-alkenyl, xe2x80x94OC(S)NR-substituted alkenyl, xe2x80x94OC(S)NR-alkynyl, xe2x80x94OC(S)NR-substituted alkynyl, xe2x80x94OC(S)NR-cycloalkyl, xe2x80x94OC(S)NR-substituted cycloalkyl, xe2x80x94OC(S)NR-aryl, xe2x80x94OC(S)NR-substituted aryl, xe2x80x94OC(S)NR-heteroaryl, xe2x80x94OC(S)NR-substituted heteroaryl, xe2x80x94OC(S)NR-heterocyclic, and xe2x80x94OC(S)NR-substituted heterocyclic where R is hydrogen, alkyl or where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cOxysulfonylaminoxe2x80x9d refers to the groups xe2x80x94OSO2NH2, xe2x80x94OSO2NRR, xe2x80x94OSO2NR-alkyl, xe2x80x94OSO2NR-substituted alkyl, xe2x80x94OSO2NR-alkenyl, xe2x80x94OSO2NR-substituted alkenyl, xe2x80x94OSO2NR-alkynyl, xe2x80x94OSO2NR-substituted alkynyl, xe2x80x94OSO2NR-cycloalkyl, xe2x80x94OSO2NR-substituted cycloalkyl, xe2x80x94OSO2NR-aryl, xe2x80x94OSO2NR-substituted aryl, xe2x80x94OSO2NR-heteroaryl, xe2x80x94OSO2NR-substituted heteroaryl, xe2x80x94OSO2NR-heterocyclic, and xe2x80x94OSO2NR-substituted heterocyclic where R is hydrogen, alkyl or where each R is joined to form, together with the nitrogen atom a heterocyclic or substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAminocarbonylaminoxe2x80x9d refers to the groups xe2x80x94NRC(O)NRR, xe2x80x94NRC(O)NR-alkyl, xe2x80x94NRC(O)NR-substituted alkyl, xe2x80x94NRC(O)NR-alkenyl, xe2x80x94NRC(O)NR-substituted alkenyl, xe2x80x94NRC(O)NR-alkynyl, xe2x80x94NRC(O)NR-substituted alkynyl, xe2x80x94NRC(O)NR-aryl, xe2x80x94NRC(O)NR-substituted aryl, xe2x80x94NRC(O)NR-cycloalkyl, xe2x80x94NRC(O)NR-substituted cycloalkyl, xe2x80x94NRC(O)NR-heteroaryl, and xe2x80x94NRC(O)NR-substituted heteroaryl, xe2x80x94NRC(O)NR-heterocyclic, and xe2x80x94NRC(O)NR-substituted heterocyclic where each R is independently hydrogen, alkyl or where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAminothiocarbonylaminoxe2x80x9d refers to the groups xe2x80x94NRC(S)NRR, xe2x80x94NRC(S)NR-alkyl, xe2x80x94NRC(S)NR-substituted alkyl, xe2x80x94NRC(S)NR-alkenyl, xe2x80x94NRC(S)NR-substituted alkenyl, xe2x80x94NRC(S)NR-alkynyl, xe2x80x94NRC(S)NR-substituted alkynyl, xe2x80x94NRC(S)NR-aryl, xe2x80x94NRC(S)NR-substituted aryl, xe2x80x94NRC(S)NR-cycloalkyl, xe2x80x94NRC(S)NR-substituted cycloalkyl, xe2x80x94NRC(S)NR-heteroaryl, and xe2x80x94NRC(S)NR-substituted heteroaryl, xe2x80x94NRC(S)NR-heterocyclic, and xe2x80x94NRC(S)NR-substituted heterocyclic where each R is independently hydrogen, alkyl or where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAminosulfonylaminoxe2x80x9d refers to the groups xe2x80x94NRSO2NRR, xe2x80x94NRSO2NR-alkyl, xe2x80x94NRSO2NR-substituted alkyl, xe2x80x94NRSO2NR-alkenyl, xe2x80x94NRSO2NR-substituted alkenyl, xe2x80x94NRSO2NR-alkynyl, xe2x80x94NRSO2NR-substituted alkynyl, xe2x80x94NRSO2NR-aryl, xe2x80x94NRSO2NR-substituted aryl, xe2x80x94NRSO2NR-cycloalkyl, xe2x80x94NRSO2NR-substituted cycloalkyl, xe2x80x94NRSO2NR-heteroaryl, and xe2x80x94NRSO2NR-substituted heteroaryl, xe2x80x94NRSO2NR-heterocyclic, and xe2x80x94NRSO2NR-substituted heterocyclic, where each R is independently hydrogen, alkyl or where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cArylxe2x80x9d or xe2x80x9cArxe2x80x9d refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2Hxe2x80x941,4-benzoxazinxe2x80x943(4H)-onexe2x80x947yl, and the like). Preferred aryls include phenyl and naphthyl.
Substituted aryl refers to aryl groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy. substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94S(O)2-alkyl, xe2x80x94S(O)2-substituted alkyl, xe2x80x94S(O)2-cycloalkyl, xe2x80x94S(O)2-substituted cycloalkyl, xe2x80x94S(O)2-alkenyl, xe2x80x94S(O)2-substituted alkenyl, xe2x80x94S(O)2-aryl, xe2x80x94S(O)2-substituted aryl, xe2x80x94S(O)2-heteroaryl, xe2x80x94S(O)2-substituted heteroaryl, xe2x80x94S(O)2-heterocyclic, xe2x80x94S(O)2-substituted heterocyclic, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and dixe2x80x94(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cAryloxyxe2x80x9d refers to the group arylxe2x80x94Oxe2x80x94 which includes, by way of example, phenoxy, naphthoxy, and the like.
xe2x80x9cSubstituted aryloxyxe2x80x9d refers to substituted arylxe2x80x94Oxe2x80x94 groups.
xe2x80x9cAryloxyarylxe2x80x9d refers to the group -arylxe2x80x94O-aryl.
xe2x80x9cSubstituted aryloxyarylxe2x80x9d refers to aryloxyaryl groups substituted with from 1 to 3 substituents on either or both aryl rings selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94S(O)2-alkyl, xe2x80x94S(O)2-substituted alkyl, xe2x80x94S(O)2-cycloalkyl, xe2x80x94S(O)2-substituted cycloalkyl, xe2x80x94S(O)2-alkenyl, xe2x80x94S(O)2-substituted alkenyl, xe2x80x94S(O)2-aryl, xe2x80x94S(O)2-substituted aryl, xe2x80x94S(O)2-heteroaryl, xe2x80x94S(O)2-substituted heteroaryl, xe2x80x94S(O)2-heterocyclic, xe2x80x94S(O)2-substituted heterocyclic, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2- NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2-NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and dixe2x80x94(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cCycloalkylxe2x80x9d refers to cyclic alkyl groups of from 3 to 8 carbon atoms having a single cyclic ring including, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like. Excluded from this definition are multi-ring alkyl groups such as adamantanyl, etc.
xe2x80x9cCycloalkenylxe2x80x9d refers to cyclic alkenyl groups of from 3 to 8 carbon atoms having single or multiple unsaturation but which are not aromatic.
xe2x80x9cSubstituted cycloalkylxe2x80x9d and xe2x80x9csubstituted cycloalkenylxe2x80x9d refer to a cycloalkyl and cycloalkenyl groups, preferably of from 3 to 8 carbon atoms, having from 1 to 5 substituents selected from the group consisting of oxo (xe2x95x90O), thioxo (xe2x95x90S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and dixe2x80x94(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkynyl/substituted alkynyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cCycloalkoxyxe2x80x9d refers to xe2x80x94O-cycloalkyl groups.
xe2x80x9cSubstituted cycloalkoxyxe2x80x9d refers to xe2x80x94O-substituted cycloalkyl groups.
xe2x80x9cCycloalkenoxyxe2x80x9d refers to xe2x80x94O-cycloalkenyl groups.
xe2x80x9cSubstituted cycloalkenoxyxe2x80x9d refers to xe2x80x94O-substituted cycloalkenyl groups.
xe2x80x9cGuanidinoxe2x80x9d refers to the groups xe2x80x94NRC(=NR)NRR, xe2x80x94NRC(xe2x95x90NR)NR-alkyl, xe2x80x94NRC(xe2x95x90NR)NR-substituted alkyl, xe2x80x94NRC(xe2x95x90NR)NR-alkenyl, xe2x80x94NRC(xe2x95x90NR)NR-substituted alkenyl, xe2x80x94NRC(xe2x95x90NR)NR-alkynyl, xe2x80x94NRC(xe2x95x90NR)NR-substituted alkynyl, xe2x80x94NRC(xe2x95x90NR)NR-aryl, xe2x80x94NRC(xe2x95x90NR)NR-substituted aryl, xe2x80x94NRC(xe2x95x90NR)NR-cycloalkyl, xe2x80x94NRC(xe2x95x90NR)NR-heteroaryl, xe2x80x94NRC(xe2x95x90NR)NR-substituted heteroaryl, xe2x80x94NRC(xe2x95x90NR)NR-heterocyclic, and xe2x80x94NRC(xe2x95x90NR)NR-substituted heterocyclic where each R is independently hydrogen and alkyl as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cGuanidinosulfonexe2x80x9d refers to the groups xe2x80x94NRC(xe2x95x90NR)NRSO2-alkyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted alkyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-alkenyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted alkenyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-alkynyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted alkynyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-aryl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted aryl, xe2x80x94NRC(xe2x95x90NR)NRSO2-cycloalkyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted cycloalkyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-heteroaryl, and xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted heteroaryl, xe2x80x94NRC(xe2x95x90NR)NRSO2-heterocyclic, and xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted heterocyclic where each R is independently hydrogen and alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to fluoro, chloro, bromo and iodo and preferably is either chloro or bromo.
xe2x80x9cHeteroarylxe2x80x9d refers to an aromatic carbocyclic group of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring or oxides thereof. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Additionally, the heteroatoms of the heteroaryl group may be oxidized, i.e., to form pyridine N-oxides or 1,1-dioxoxe2x80x941,2,5-thiadiazoles and the like. Preferred heteroaryls include pyridyl, pyrrolyl, indolyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1-oxoxe2x80x941,2,5-thiadiazolyl and 1,1-dioxoxe2x80x941,2,5-thiadiazolyl. The term xe2x80x9cheteroaryl having two nitrogen atoms in the heteroaryl ringxe2x80x9d refers to a heteroaryl group having two, and only two, nitrogen atoms in the heteroaryl ring and optionally containing 1 or 2 other heteroatoms in the heteroaryl ring, such as oxygen or sulfur.
xe2x80x9cSubstituted heteroarylxe2x80x9d refers to heteroaryl groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94S(O)2-alkyl, xe2x80x94S(O)2-substituted alkyl, xe2x80x94S(O)2-cycloalkyl, xe2x80x94S(O)2-substituted cycloalkyl, xe2x80x94S(O)2-alkenyl, xe2x80x94S(O)2-substituted alkenyl, xe2x80x94S(O)2-aryl, xe2x80x94S(O)2-substituted aryl, xe2x80x94S(O)2-heteroaryl, xe2x80x94S(O)2-substituted heteroaryl, xe2x80x94S(O)2-heterocyclic, xe2x80x94S(O)2-substituted heterocyclic, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and dixe2x80x94(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with xe2x80x94SONRR where R is hydrogen or alkyl.
xe2x80x9cHeteroaryloxyxe2x80x9d refers to the group xe2x80x94O-heteroaryl and xe2x80x9csubstituted heteroaryloxyxe2x80x9d refers to the group xe2x80x94O-substituted heteroaryl.
xe2x80x9cHeterocyclexe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d refers to a saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring wherein, in fused ring systems, one or more of the rings can be aryl or heteroaryl.
xe2x80x9cSubstituted heterocyclicxe2x80x9d refers to heterocycle groups which are substituted with from 1 to 3 substituents selected from the group consisting of oxo (xe2x95x90O), thioxo (xe2x95x90S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and dixe2x80x94(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkynyl/substituted alkynyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl.
Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholino, thiomorpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.
xe2x80x9cHeterocyclyloxyxe2x80x9d refers to the group xe2x80x94O-heterocyclic and xe2x80x9csubstituted heterocyclyloxyxe2x80x9d refers to the group xe2x80x94O-substituted heterocyclic.
xe2x80x9cThiolxe2x80x9d refers to the group xe2x80x94SH.
xe2x80x9cThioalkylxe2x80x9d refers to the groups xe2x80x94S-alkyl
xe2x80x9cSubstituted thioalkylxe2x80x9d refers to the group xe2x80x94S-substituted alkyl.
xe2x80x9cThiocycloalkylxe2x80x9d refers to the groups xe2x80x94S-cycloalkyl.
xe2x80x9cSubstituted thiocycloalkylxe2x80x9d refers to the group xe2x80x94S-substituted cycloalkyl.
xe2x80x9cThioarylxe2x80x9d refers to the group xe2x80x94S-aryl and xe2x80x9csubstituted thioarylxe2x80x9d refers to the group xe2x80x94S-substituted aryl.
xe2x80x9cThioheteroarylxe2x80x9d refers to the group xe2x80x94S-heteroaryl and xe2x80x9csubstituted thioheteroarylxe2x80x9d refers to the group xe2x80x94S-substituted heteroaryl.
xe2x80x9cThioheterocyclicxe2x80x9d refers to the group xe2x80x94S-heterocyclic and xe2x80x9csubstituted thioheterocyclicxe2x80x9d refers to the group xe2x80x94S-substituted heterocyclic.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d refers to pharmaceutically acceptable salts of a compound of Formula I which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
The compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
Furthermore, the compounds of this invention will typically contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
In a preferred method of synthesis, the compounds of this invention are prepared by coupling an amino acid derivative of the formula: 
where R3 and R3xe2x80x2 are as defined herein and P1 is a carboxylic acid protecting group (such as an alkyl group, i.e. methyl, ethyl and the like), with a suitably functionalized heteroaryl or heterocyclic intermediate. For example, such coupling reactions may be performed by displacing a leaving group, such as chloro, bromo, iodo, tosyl and the like, from the heteroaryl or heterocyclic intermediate with the amino group of the amino acid derivative; or by reductive alkylation of the amino group of amino acid derivative with a carbonyl-functionalized intermediate. Such coupling reactions are well-known to those skilled in the art.
By way of illustration, the synthesis of a representative compound of formula I is shown in Scheme 1. 
As shown in Scheme 1, 5-nitrouracil, 1, (commercially available from Aldrich Chemical Company, Milwaukee, Wis. USA) is treated with phosphorus oxychloride and N,N-dimethylaniline according to the procedure described in Whittaker, J. Chem. Soc. 1951, 1565 to give 1,3-dichloroxe2x80x944-nitropyrimidine, 2.
1,3-Dichloroxe2x80x944-nitropyrimidine, 2, is then reacted with about one molar equivalent of an amino acid derivative of the formula: H2Nxe2x80x94CH(R3)C(O)X where R3 and X are as defined herein or X is xe2x80x94OP1 where P1 is a carboxylic acid protecting group, in the presence of a trialkylamine, such as diisopropylethylamine (DIEA). Typically, this reaction is conducted in an inert diluent, such as dichloromethane, at a temperature ranging from about 0xc2x0 C. to about 10xc2x0 C. for about 5 min. to about 6 hours to afford intermediate 3.
The nitro group of intermediate 3 is then reduced using a conventional reducing agent, such as hydrogen and a palladium on carbon catalyst. When hydrogen and palladium on carbon are employed as the reducing agent, the chloro group of intermediate 3 is also removed. This reaction is typically conducted by contacting 3 with a Degussa-type palladium on carbon catalyst (typically 20%) and excess sodium bicarbonate in an inert diluent. such as methanol, under hydrogen (typically about 55 psi) for about 12 to 36 hours at ambient temperature to afford amino intermediate 4.
Amino intermediate 4 is then reacted with a sulfonyl chloride of the formula: R5xe2x80x94S(O)2xe2x80x94Cl, where R5 is as defined herein, to provide sulfonamide intermediate 5. This reaction is typically conducted by reacting the amino intermediate 4 with at least one equivalent, preferably about 1.1 to about 2 equivalents, of the sulfonyl chloride in an inert diluent such as dichloromethane and the like. Generally, the reaction is conducted at a temperature ranging from about xe2x88x9270xc2x0 C. to about 40xc2x0 C. for about 1 to about 24 hours. Preferably, this reaction is conducted in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Alternatively, the reaction can be conducted under Schotten-Baumann-type conditions using aqueous alkali, such as sodium hydroxide and the like, as the base. Upon completion of the reaction, the resulting sulfonamide 5 is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like.
Other heteroaryl intermediates may also be employed in the above described reactions including, but not limited to, 2-chloroxe2x80x943-nitropyrazine (J. Med. Chem. 1984, 27, 1634); 4-chloroxe2x80x945-nitroimidazole (J. Chem. Soc. 1930, 268); and the like.
The amino acid derivatives employed in the above reactions are either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures. For example, amino acid derivatives can be prepared by C-alkylating commercially available diethyl 2-acetamidomalonate (Aldrich, Milwaukee, Wis., USA) with an alkyl or substituted alkyl halide. This reaction is typically conducted by treating the diethyl 2-acetamidomalonate with at least one equivalent of sodium ethoxide and at least one equivalent of an alkyl or substituted alkyl halide in refluxing ethanol for about 6 to about 12 hours. The resulting C-alkylated malonate is then deacetylated, hydrolyzed and decarboxylated by heating in aqueous hydrochloric acid at reflux for about 6 to about 12 hours to provide the amino acid, typically as the hydrochloride salt.
Examples of amino acid derivatives suitable for use in the above reactions include, but are not limited to, L-alanine methyl ester, L-isoleucine methyl ester, L-leucine methyl ester, L-valine methyl ester, xcex2-tert-butyl-L- aspartic acid methyl ester, L-asparagine tert-butyl ester, xcex5-Boc-L-lysine methyl ester, xcex5-Cbz-L-lysine methyl ester, xcex3-tert-butyl-L-glutamic acid methyl ester, L-glutamine tert-butyl ester, Lxe2x80x94(N-methyl)histidine methyl ester, Lxe2x80x94(N-benzyl)histidine methyl ester, L-methionine methyl ester, Lxe2x80x94(O-benzyl)serine methyl ester, L-tryptophan methyl ester, L-phenylalanine methyl ester, L-phenylalanine isopropyl ester, L-phenylalanine benzyl ester, L-phenylalaninamide, N-methyl-L-phenylalanine benzyl ester, 3-carboxy-D,L-phenylalanine methyl ester, 4-carboxy-D,L-phenylalanine methyl ester, Lxe2x80x944-chlorophenylalanine methyl ester, Lxe2x80x944xe2x80x94(3-dimethylaminopropyloxy)-phenylalanine methyl ester, Lxe2x80x944-iodophenylalanine methyl ester, Lxe2x80x943,4-methylenedioxyphenylalanine methyl ester, Lxe2x80x943,4-ethylenedioxyphenylalanine methyl ester, Lxe2x80x944-nitrophenylalanine methyl ester, L-tyrosine methyl ester, D,L-homophenylalanine methyl ester, Lxe2x80x94(O-methyl)tyrosine methyl ester, Lxe2x80x94(O-tert-butyl)tyrosine methyl ester, Lxe2x80x94(O-benzyl)tyrosine methyl ester, Lxe2x80x943,5-diiodotyrosine methyl ester, Lxe2x80x943-iodotyrosine methyl ester, xcex2xe2x80x94(1-naphthyl)-L-alanine methyl ester, xcex2xe2x80x94(2-naphthyl)-L-alanine methyl ester, xcex2xe2x80x94(2-thienyl)-L-alanine methyl ester, xcex2-cyclohexyl-L-alanine methyl ester, xcex2xe2x80x94(2-pyridyl)-L-alanine methyl ester, xcex2xe2x80x94(3-pyridyl)-L-alanine methyl ester, xcex2xe2x80x94(4-pyridyl)-L-alanine methyl ester, xcex2xe2x80x94(2-thiazolyl)-D,L-alanine methyl ester, xcex2xe2x80x94(1,2,4-triazolxe2x80x943-yl)-D,L-alanine methyl ester, and the like. If desired, of course, other esters or amides of the above-described compounds may also be employed.
Additionally, xcex1-hydroxy and xcex1-thio carboxylic acids may also be employed in the above-described reactions. Such compounds are well-known in the art and are either commercially available or may be prepared from commercially available starting materials using conventional reagents and reaction conditions.
The sulfonyl chlorides employed in the above reaction are also either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures. Such compounds are typically prepared from the corresponding sulfonic acid, i.e., from compounds of the formula R5xe2x80x94SO3H where R5 is as defined above, using phosphorous trichloride and phosphorous pentachloride. This reaction is generally conducted by contacting the sulfonic acid with about 2 to 5 molar equivalents of phosphorous trichloride and phosphorous pentachloride, either neat or in an inert solvent, such as dichloromethane, at temperature in the range of about 0xc2x0 C. to about 80xc2x0 C. for about 1 to about 48 hours to afford the sulfonyl chloride. Alternatively, the sulfonyl chloride can be prepared from the corresponding thiol compound, i.e., from compounds of the formula R5xe2x80x94SH where R5 is as defined herein, by treating the thiol with chlorine (Cl2) and water under conventional reaction conditions.
Examples of sulfonyl chlorides suitable for use in this invention include, but are not limited to, methanesulfonyl chloride, 2-propanesulfonyl chloride, 1-butanesulfonyl chloride, benzenesulfonyl chloride, 1-naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride, p-toluenesulfonyl chloride, a-toluenesulfonyl chloride, 4-acetamidobenzenesulfonyl chloride, 4-amidinobenzenesulfonyl chloride, 4-tert-butylbenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 2-carboxybenzenesulfonyl chloride, 4-cyanobenzenesulfonyl chloride, 3,4-dichlorobenzenesulfonyl chloride, 3,5-dichlorobenzenesulfonyl chloride, 3,4-dimethoxybenzenesulfonyl chloride, 3,5-ditrifluoromethylbenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 2-methoxycarbonylbenzenesulfonyl chloride, 4-methylamidobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 4-thioamidobenzenesulfonyl chloride, 4-trifluoromethylbenzenesulfonyl chloride, 4-trifluoromethoxybenzenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2-phenylethanesulfonyl chloride, 2-thiophenesulfonyl chloride, 5-chloroxe2x80x942-thiophenesulfonyl chloride, 2,5-dichloroxe2x80x944-thiophenesulfonyl chloride, 2-thiazolesulfonyl chloride, 2-methylxe2x80x944-thiazolesulfonyl chloride, 1-methylxe2x80x944-imidazolesulfonyl chloride, 1-methylxe2x80x944-pyrazolesulfonyl chloride, 5-chloro- 1, 3-dimethylxe2x80x944-pyrazolesulfonyl chloride, 3-pyridinesulfonyl chloride, 2-pyrimidinesulfonyl chloride and the like. If desired, a sulfonyl fluoride, sulfonyl bromide or sulfonic acid anhydride may be used in place of the sulfonyl chloride in the above reaction to form the sulfonamide intermediate 5.
If desired, sulfonamide intermediate 5 can be alkylated at the sulfonamide nitrogen atom to provide compound 6. For example, 5 can be contacted with excess diazomethane (generated, for example, using 1-methylxe2x80x943-nitroxe2x80x941-nitrosoguanidine and sodium hydroxide) to afford 6 where R6 is methyl. Other conventional alkylation procedures and reagents may also be employed to prepare various compounds of this invention.
In another preferred embodiment, compounds of this invention may be prepared by displacement of a leaving group as shown in Scheme 2: 
where R3, Q and X are as defined herein; Axe2x80x2 is heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic containing two nitrogen atoms in the heteroaryl or heterocyclic ring; and L1 is a leaving group, such as chloro, bromo, iodo, sulfonate ester and the like.
Typically, this reaction is conducted by combining approximately stoichiometric equivalents of 7 and 8 in a suitable inert diluent such as water, dimethylsulfoxide (DMSO) and the like, with an excess of a suitable base such as sodium bicarbonate, sodium hydroxide, etc. to scavenge the acid generated by the reaction. The reaction is preferably conducted at from about 25xc2x0 C. to about 100xc2x0 C. until reaction completion which typically occurs within 1 to about 24 hours. This reaction is further described in U.S. Pat. No. 3,598,859, which is incorporated herein by reference in its entirety. Upon reaction completion, the product 9 is recovered by conventional methods including precipitation, chromatography, filtration and the like.
In still another alternative embodiment, compounds of this invention in which Q is NR4 can be prepared by reductive amination of a suitable 2-oxocarboxylic acid ester, 10, such as a pyruvate ester, as shown in Scheme 3: 
where Axe2x80x2, R3 and X are as defined herein.
Generally, this reaction is conducted by combining equamolar amounts of 10 and 11 in an inert diluent such as methanol, ethanol and the like under conditions which provide for imine formation (not shown). The imine formed is then reduced under conventional conditions by a suitable reducing agent such as sodium cyanoborohydride, H2/palladium on carbon and the like to form the product 12. In a particularly preferred embodiment, the reducing agent is H2/palladium on carbon which is incorporated into the initial reaction medium thereby permitting imine reduction in situ in a one pot procedure to provide 12. The reaction is preferably conducted at from about 20xc2x0 C. to about 80xc2x0 C. at a pressure of from 1 to 10 atmospheres until reaction completion which typically occurs within 1 to about 24 hours. Upon reaction completion, the product 12 is recovered by conventional methods including chromatography, filtration and the like.
Alternatively, certain compounds of this invention can be prepared via a rhodium-catalyzed insertion reaction as shown in Scheme 4: 
where Axe2x80x3 is heteroaryl or substituted heteroaryl containing two nitrogen atoms in the heteroaryl ring, and R3 and X (preferably alkoxy) are as defined herein. Typically, this reaction is conducted using rhodium acetate dimer, Rh2(OAc)4, in an inert diluent such as toluene at a temperature ranging from about 25xc2x0 C. to about 80xc2x0 C. for about I to 12 hours to afford 15. This reaction is described further in B. R. Henke et. al., J. Med. Chem. 1998, 41, 5020-5036 and references cited therein.
Similarly, certain compounds of this invention can be prepared by the copper-catalyzed coupling reaction shown in Scheme 5: 
where Axe2x80x3 is as defined herein, X3 is halogen, such as chloro, bromo or iodo (preferably iodo), and R3 and X (preferably alkoxy) are as defined herein. Typically, this reaction is conducted using copper iodide (CuI) and potassium carbonate in an inert diluent such as N,N-dimethyl acetamide (DMA) at a temperature ranging from about 60xc2x0 C. to about 120xc2x0 C. for about 12 to 36 hours to afford 15. This reaction is described further in D. Ma et. al., J. Am. Chem. Soc. 1998, 120, 12459-12467 and references cited therein.
For ease of synthesis, the compounds of this invention are typically prepared as an ester, i.e., where X is an alkoxy or substituted alkoxy group and the like. If desired, the ester group can be hydrolysed using conventional conditions and reagents to provide the corresponding carboxylic acid. Typically, this reaction is conducted by treating the ester with at least one equivalent of an alkali metal hydroxide, such as lithium, sodium or potassium hydroxide, in an inert diluent, such as methanol or mixtures of methanol and water, at a temperature ranging about 0xc2x0 C. to about 24xc2x0 C. for about 1 to about 12 hours. Alternatively, benzyl esters may be removed by hydrogenolysis using a palladium catalyst, such as palladium on carbon, and tert-butyl esters can be removed using formic acid to afford the corresponding carboxylic acid.
As will be apparent to those skilled in the art, other functional groups present on any of the substituents of the compounds of formulas I-VII can be readily modified or derivatized either before or after the above-described synthetic reactions using well-known synthetic procedures. For example, a nitro group present on a substituent of a compound of formula I-VII or an intermediate thereof may be readily reduced by hydrogenation in the presence of a palladium catalyst, such as palladium on carbon, to provide the corresponding amino group. This reaction is typically conducted at a temperature of from about 20xc2x0 C. to about 50xc2x0 C. for about 6 to about 24 hours in an inert diluent, such as methanol. Compounds having a nitro group on the R3 and/or R3 substituent can be prepared, for example, by using a 4-nitrophenylalanine derivative and the like in the above-described coupling reactions.
Similarly, a pyridyl group can be hydrogenated in the presence of a platinum catalyst, such as platinum oxide, in an acidic diluent to provide the corresponding piperidinyl analogue. Generally, this reaction is conducted by treating the pyridine compound with hydrogen at a pressure ranging from about 20 psi to about 60 psi, preferably about 40 psi, in the presence of the catalyst at a temperature of about 20xc2x0 C. to about 50xc2x0 C. for about 2 to about 24 hours in an acidic diluent, such as a mixture of methanol and aqueous hydrochloric acid.
Additionally, when the R3 and/or R3xe2x80x2 substituent of a compound of formula I-VII or an intermediate thereof contains a primary or secondary amino group, such amino groups can be further derivatized either before or after the above coupling reactions to provide, by way of example, amides, sulfonamides, ureas, thioureas, carbamates, secondary or tertiary amines and the like. Compounds having a primary amino group on the R3 and/or R3xe2x80x2 substituent may be prepared, for example, by reduction of the corresponding nitro compound as described above.
By way of illustration, a compound of formula I-VII or an intermediate thereof having a substituent containing a primary or secondary amino group, such as where R3 is a (4-aminophenyl)methyl group, can be readily N-acylated using conventional acylating reagents and conditions to aprovide the corresponding amide. This acylation reaction is typically conducted by treating the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of a carboxylic acid in the presence of a coupling reagent such as a carbodiimide, BOP reagent (benzotriazolxe2x80x941-yloxy-tris(dimethylamino)phosphonium hexafluorophosphonate) and the like, in an inert diluent, such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N,N-dimethylformamide and the like, at a temperature ranging from about 0xc2x0 C. to about 37xc2x0 C. for about 4 to about 24 hours. Preferably, a promoter, such as N-hydroxysuccinimide, 1-hydroxy-benzotriazole and the like, is used to facilitate the acylation reaction. Examples of carboxylic acids suitable for use in this reaction include, but are not limited to, N-tert-butyloxycarbonylglycine, N-tert-butyloxycarbonyl-L-phenylalanine, N-tert-butyloxycarbonyl-L-aspartic acid benzyl ester, benzoic acid, N-tert-butyloxycarbonylisonipecotic acid, N-methylisonipecotic acid, N-tert-butyloxycarbonylnipecotic acid, N-tert-butyloxycarbonyl-L-tetrahydroisoquinolinexe2x80x943-carboxylic acid, Nxe2x80x94(toluenexe2x80x944-sulfonyl)-L-proline and the like.
Alternatively, a compound of formula I-VII or an intermediate thereof containing a primary or secondary amino group can be N-acylated using an acyl halide or a carboxylic acid anhydride to form the corresponding amide. This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the acyl halide or carboxylic acid anhydride in an inert diluent, such as dichloromethane, at a temperature ranging from about xe2x88x9270xc2x0 C. to about 40xc2x0 C. for about 1 to about 24 hours. If desired, an acylation catalyst such as 4xe2x80x94(N,N-dimethylamino)pyridine may be used to promote the acylation reaction. The acylation reaction is preferably conducted in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Alternatively, the reaction can be conducted under Schotten-Baumann-type conditions using aqueous alkali, such as sodium hydroxide and the like.
Examples of acyl halides and carboxylic acid anhydrides suitable for use in this reaction include, but are not limited to, 2-methylpropionyl chloride, trimethylacetyl chloride, phenylacetyl chloride, benzoyl chloride, 2-bromobenzoyl chloride, 2-methylbenzoyl chloride, 2-trifluoro-methylbenzoyl chloride, isonicotinoyl chloride, nicotinoyl chloride, picolinoyl chloride, acetic anhydride, succinic anhydride, and the like. Carbamyl chlorides, such as N,N-dimethylcarbamyl chloride, N,N-diethylcarbamyl chloride and the like, can also be used in this reaction to provide ureas. Similarly, dicarbonates, such as di-tert-butyl dicarbonate, may be employed to provide carbamates.
In a similar manner, a compound of formula I-VII or an intermediate thereof containing a primary or secondary amino group may be N-sulfonated to form a sulfonamide using a sulfonyl halide or a sulfonic acid anhydride. Sulfonyl halides and sulfonic acid anhydrides suitable for use in this reaction include, but are not limited to, methanesulfonyl chloride, chloromethanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, and the like. Similarly, sulfamoyl chlorides, such as dimethylsulfamoyl chloride, can be used to provide sulfamides (e.g.,  greater than Nxe2x80x94SO2xe2x80x94N less than ).
Additionally, a primary and secondary amino group present on a substituent of a compound of formula I-VII or an intermediate thereof can be reacted with an isocyanate or a thioisocyanate to give a urea or thiourea, respectively. This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the isocyanate or thioisocyanate in an inert diluent, such as toluene and the like, at a temperature ranging from about 24xc2x0 C. to about 37xc2x0 C. for about 12 to about 24 hours. The isocyanates and thioisocyanates used in this reaction are commercially available or can be prepared from commercially available compounds using well-known synthetic procedures. For example, isocyanates and thioisocyanates are readily prepared by reacting the appropriate amine with phosgene or thiophosgene. Examples of isocyanates and thioisocyanates suitable for use in this reaction include, but are not limited to, ethyl isocyanate, n-propyl isocyanate, 4-cyanophenyl isocyanate, 3-methoxyphenyl isocyanate, 2-phenylethyl isocyanate, methyl thioisocyanate, ethyl thioisocyanate, 2-phenylethyl thioisocyanate, 3-phenylpropyl thioisocyanate, 3xe2x80x94(N,N-diethylamino)propyl thioisocyanate, phenyl thioisocyanate, benzyl thioisocyanate, 3-pyridyl thioisocyanate, fluorescein isothiocyanate (isomer I) and the like.
Furthermore, when a compound of formula I-VII or an intermediate thereof contains a primary or secondary amino group, the amino group can be reductively alkylated using aldehydes or ketones to form a secondary or tertiary amino group. This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.5 equivalents, of an aldehyde or ketone and at least one equivalent based on the amino compound of a metal hydride reducing agent, such as sodium cyanoborohydride, in an inert diluent, such as methanol, tetrahydrofuran, mixtures thereof and the like, at a temperature ranging from about 0xc2x0 C. to about 50xc2x0 C. for about 1 to about 72 hours. Aldehydes and ketones suitable for use in this reaction include, by way of example, benzaldehyde, 4-chlorobenzaldehyde, valeraldehyde and the like.
In a similar manner, when a compound of formula I-VII or an intermediate thereof has a substituent containing a hydroxyl group, the hydroxyl group can be further modified or derivatized either before or after the above coupling reactions to provide, by way of example, ethers, carbamates and the like. Compounds having a hydroxyl group on the R3 substituent, for example, can be prepared using an amino acid derivative derived from tyrosine and the like in the above-described reactions.
By way of example, a compound of formula I-VII or an intermediate thereof having a substituent containing a hydroxyl group, such as where R3 is a (4-hydroxyphenyl)methyl group, can be readily O-alkylated to form ethers. This O-alkylation reaction is typically conducted by contacting the hydroxy compound with a suitable alkali or alkaline earth metal base, such as potassium carbonate, in an inert diluent, such as acetone, 2-butanone and the like, to form the alkali or alkaline earth metal salt of the hydroxyl group. This salt is generally not isolated, but is reacted in situ with at least one equivalent of an alkyl or substituted alkyl halide or sulfonate, such as an alkyl chloride, bromide, iodide, mesylate or tosylate, to afford the ether. Generally, this reaction is conducted at a temperature ranging from about 60xc2x0 C. to about 150xc2x0 C. for about 24 to about 72 hours. Preferably, a catalytic amount of sodium or potassium iodide is added to the reaction mixture when an alkyl chloride or bromide is employed in the reaction.
Examples of alkyl or substituted alkyl halides and sulfonates suitable for use in this reaction include, but are not limited to, tert-butyl bromoacetate, N-tert-butyl chloroacetamide, 1-bromoethylbenzene, ethyl xcex1-bromophenylacetate, 2xe2x80x94(N-ethyl-N-phenylamino)ethyl chloride, 2xe2x80x94(N,N-ethylamino)ethyl chloride, 2xe2x80x94(N,N-diisopropylamino)ethyl chloride, 2xe2x80x94(N,N-dibenzylamino)ethyl chloride, 3xe2x80x94(N,N-ethylamino)propyl chloride, 3xe2x80x94(N-benzyl-N-methylamino)propyl chloride, Nxe2x80x94(2-chloroethyl)morpholine, 2xe2x80x94(hexamethyleneimino)ethyl chloride; 3xe2x80x94(N-methylpiperazine)propyl chloride, 1xe2x80x94(3-chlorophenyl)xe2x80x944xe2x80x94(3-chloropropyl)piperazine, 2xe2x80x94(4-hydroxyxe2x80x944-phenylpiperidine)ethyl chloride, N-tert-butyloxycarbonylxe2x80x943-piperidinemethyl tosylate, and the like.
Alternatively, a hydroxyl group present on a substituent of a compound of formula I-VII or an intermediate thereof can be O-alkylating using the Mitsunobu reaction. In this reaction, an alcohol, such as 3xe2x80x94(N,N-dimethylamino)xe2x80x941-propanol and the like, is reacted with about 1.0 to about 1.3 equivalents of triphenylphosphine and about 1.0 to about 1.3 equivalents of diethyl azodicarboxylate in an inert diluent, such as tetrahydrofuran, at a temperature ranging from about xe2x88x9210xc2x0 C. to about 5xc2x0 C. for about 0.25 to about 1 hour. About 1.0 to about 1.3 equivalents of a hydroxy compound, such as N-tert-butyltyrosine methyl ester, is then added and the reaction mixture is stirred at a temperature of about 0xc2x0 C. to about 30xc2x0 C. for about 2 to about 48 hours to provide the O-alkylated product.
In a similar manner, a compound of formula I-VII or an intermediate thereof containing an aryl hydroxy group can be reacted with an aryl iodide to provide a diaryl ether. Generally, this reaction is conducted by forming the alkali metal salt of the hydroxyl group using a suitable base, such as sodium hydride, in an inert diluent such as xylenes at a temperature of about xe2x88x9225xc2x0 C. to about 10xc2x0 C. The salt is then treated with about 1.1 to about 1.5 equivalents of cuprous bromide dimethyl sulfide complex at a temperature ranging from about 10xc2x0 C. to about 30xc2x0 C. for about 0.5 to about 2.0 hours, followed by about 1.1 to about 1.5 equivalents of an aryl iodide, such as sodium 2-iodobenzoate and the like. The reaction is then heated to about 70xc2x0 C. to about 150xc2x0 C. for about 2 to about 24 hours to provide the diaryl ether.
Additionally, a hydroxy-containing compound can also be readily derivatized to form a carbamate. In one method for preparing such carbamates, a hydroxy compound of formula I-VII or an intermediate thereof is contacted with about 1.0 to about 1.2 equivalents of 4-nitrophenyl chloroformate in an inert diluent, such as dichloromethane, at a temperature ranging from about xe2x88x9225xc2x0 C. to about 0xc2x0 C. for about 0.5 to about 2.0 hours. Treatment of the resulting carbonate with an excess, preferably about 2 to about 5 equivalents, of a trialkylamine, such as triethylamine, for about 0.5 to 2 hours, followed by about 1.0 to about 1.5 equivalents of a primary or secondary amine provides the carbamate. Examples of amines suitable for using in this reaction include, but are not limited to, piperazine, 1-methylpiperazine, 1-acetylpiperazine, morpholine, thiomorpholine, pyrrolidine, piperidine and the like.
Alternatively, in another method for preparing carbamates, a hydroxy-containing compound is contacted with about 1.0 to about 1.5 equivalents of a carbamyl chloride in an inert diluent, such as dichloromethane, at a temperature ranging from about 25xc2x0 C. to about 70xc2x0 C. for about 2 to about 72 hours. Typically, this reaction is conducted in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Additionally, at least one equivalent (based on the hydroxy compound) of 4xe2x80x94(N,N-dimethylamino)pyridine is preferably added to the reaction mixture to facilitate the reaction. Examples of carbamyl chlorides suitable for use in this reaction include, by way of example, dimethylcarbamyl chloride, diethylcarbamyl chloride and the like.
Likewise, when a compound of formula I-VII or an intermediate thereof contains a primary or secondary hydroxyl group, such hydroxyl groups can be readily converted into a leaving group and displaced to form, for example, amines, sulfides and fluorides. Generally, when a chiral compound is employed in these reactions, the stereochemistry at the carbon atom attached to the derivatized hydroxyl group is typically inverted.
These reactions are typically conducted by first converting the hydroxyl group into a leaving group, such as a tosylate, by treatment of the hydroxy compound with at least one equivalent of a sulfonyl halide, such as p-toluenesulfonyl chloride and the like, in pyridine. This reaction is generally conducted at a temperature of from about 0xc2x0 C. to about 70xc2x0 C. for about 1 to about 48 hours. The resulting tosylate can then be readily displaced with sodium azide, for example, by contacting the tosylate with at least one equivalent of sodium azide in an inert diluent, such as a mixture of N,N-dimethylformamide and water, at a temperature ranging from about 0xc2x0 C. to about 37xc2x0 C. for about 1 to about 12 hours to provide the corresponding azido compound. The azido group can then be reduced by, for example, hydrogenation using a palladium on carbon catalyst to provide the amino (xe2x80x94NH2) compound.
Similarly, a tosylate group can be readily displaced by a thiol to form a sulfide. This reaction is typically conducted by contacting the tosylate with at least one equivalent of a thiol, such as thiophenol, in the presence of a suitable base, such as 1,8-diazabicyclo[5.4.0]undecxe2x80x947-ene (DBU), in an inert diluent, such as N,N-dimethylformamide, at a temperature of from about 0xc2x0 C. to about 37xc2x0 C. for about 1 to about 12 hours to provide the sulfide. Additionally, treatment of a tosylate with morpholinosulfur trifluoride in an inert diluent, such as dichloromethane, at a temperature ranging from about 0xc2x0 C. to about 37xc2x0 C. for about 12 to about 24 hours affords the corresponding fluoro compound.
Furthermore, a compound of formula I-VII or an intermediate thereof having a substituent containing an iodoaryl group, for example, when R3 is a (4-iodophenyl)methyl group, can be readily converted either before or after the above coupling reactions into a biaryl compound. Typically, this reaction is conducted by treating the iodoaryl compound with about 1.1 to about 2 equivalents of an arylzinc iodide, such as 2xe2x80x94(methoxycarbonyl)phenylzinc iodide, in the presence of a palladium catalyst, such as palladium tetra(triphenylphosphine), in an inert diluent, such as tetrahydrofuran, at a temperature ranging from about 24xc2x0 C. to about 30xc2x0 C. until reaction completion. This reaction is further described, for example, in Rieke, J. Org. Chem. 1991, 56, 1445. Additional methods for preparing biaryl derivatives are disclosed in International Publication Number WO 98/53817, published Dec. 3, 1998, the disclosure of which is incorporated herein by reference in its entirety.
In some cases, the compounds of formula I-VII or intermediates thereof may contain substituents having one or more sulfur atoms. When present, such sulfur atoms can be oxidized either before or after the above coupling reactions to provide a sulfoxide or sulfone compound using conventional reagents and reaction conditions. Suitable reagents for oxidizing a sulfide compound to a sulfoxide include, by way of example, hydrogen peroxide, 3-chloroperoxybenzoic acid (MCPBA), sodium periodate and the like. The oxidation reaction is typically conducted by contacting the sulfide compound with about 0.95 to about 1.1 equivalents of the oxidizing reagent in an inert diluent, such as dichloromethane, at a temperature ranging from about xe2x88x9250xc2x0 C. to about 75xc2x0 C. for about 1 to about 24 hours. The resulting sulfoxide can then be further oxidized to the corresponding sulfone by contacting the sulfoxide with at least one additional equivalent of an oxidizing reagent, such as hydrogen peroxide, MCPBA, potassium permanganate and the like. Alternatively, the sulfone can be prepared directly by contacting the sulfide with at least two equivalents, and preferably an excess, of the oxidizing reagent. Such reactions are described further in March, xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th Ed., pp. 1201-1202, Wiley Publisher, 1992.
Other procedures and reaction conditions for preparing the compounds of this invention are described in the examples set forth below. Additionally, other procedures for preparing compounds useful in certain aspects of this invention are described in U.S. Ser. No. 09/489,378, filed on even date herewith, entitled xe2x80x9cCompounds Which Inhibit Leucocyte Adhesion Mediated by VLA-4xe2x80x9d (Attorney Docket No. 002010-525); the disclosure of which is incorporated herein by reference in its entirety.
When employed as pharmaceuticals, the compounds of this invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of formula I-VII above associated with pharmaceutically acceptable carriers. In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. The excipient employed is typically an excipient suitable for administration to human subjects or other mammals. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil, wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term xe2x80x9cunit dosage formsxe2x80x9d refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient""s symptoms, and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.